Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer

ABSTRACT

The present invention includes methods of stabilizing one or more sweet enhancers when they are exposed to a light source as well as liquid compositions containing one or more sweet enhancers and one or more photostabilizers.

CROSS-REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application is a divisional of U.S. patentapplication Ser. No. 14/670,331, filed Mar. 26, 2015, which is adivisional of U.S. patent application Ser. No. 13/208,594, filed Aug.12, 2011 (now U.S. Pat. No. 9,000,054), which claims the benefit ofpriority to U.S. Provisional Application No. 61/500,834, filed on Jun.24, 2011 and U.S. Provisional Application No. 61/373,083, filed on Aug.12, 2010, the disclosures of which are incorporated herein by referencein their entireties.

FIELD OF THE INVENTION

The invention relates to stabilization of sweet enhancers in liquidcompositions.

BACKGROUND OF THE INVENTION

The taste system provides sensory information about the chemicalcomposition of the external world. Taste transduction is one of the mostsophisticated forms of chemical-triggered sensation in animals.Signaling of taste is found throughout the animal kingdom, from simplemetazoans to the most complex of vertebrates. Mammals are believed tohave five basic taste modalities: sweet, bitter, sour, salty, and umami(the taste of monosodium glutamate, a.k.a. savory taste).

Obesity, diabetes, and cardiovascular disease are health concerns on therise globally, but are growing at alarming rates in the United States.Sugar and calories are key components that can be limited to render apositive nutritional effect on health. High-intensity sweeteners canprovide the sweetness of sugar, with various taste qualities. Becausethey are many times sweeter than sugar, much less of the sweetener isrequired to replace the sugar.

High-intensity sweeteners have a wide range of chemically distinctstructures and hence possess varying properties, such as, withoutlimitation, odor, flavor, mouthfeel, and aftertaste.

These properties, particularly flavor and aftertaste, are well known tovary over the time of tasting, such that each temporal profile issweetener-specific (Tunaley, A., “Perceptual Characteristics ofSweeteners”, Progress in Sweeteners, T. H. Grenby, Ed. Elsevier AppliedScience, 1989).

Sweeteners such as saccharin and6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt(acesulfame potassium) are commonly characterized as having bitterand/or metallic aftertastes. Products prepared with 2,4-dihydroxybenzoicacid are claimed to display reduced undesirable aftertastes associatedwith sweeteners, and do so at concentrations below those concentrationsat which their own tastes are perceptible. Also, high intensitysweeteners such as sucralose and aspartame are reported to havesweetness delivery problems, i.e., delayed onset and lingering ofsweetness (S. G. Wiet, et al., J. Food Sci., 58(3):599-602, 666 (1993)).

It has been reported that an extra-cellular domain, e.g., the Venusflytrap domain of a chemosensory receptor, especially one or moreinteracting sites within the Venus flytrap domain, is a suitable targetfor compounds or other entities to modulate the chemosensory receptorand/or its ligands. Certain compounds have been reported to havesuperior sweet taste enhancing properties and are described in thepatent applications listed below.

(1) U.S. patent application Ser. No. 11/760,592, entitled “Modulation ofChemosensory Receptors and Ligands Associated Therewith”, filed Jun. 8,2007; (2) U.S. patent application Ser. No. 11/836,074, entitled“Modulation of Chemosensory Receptors and Ligands Associated Therewith”,filed Aug. 8, 2007; (3) U.S. Patent Application Ser. No. 61/027,410,entitled “Modulation of Chemosensory Receptors and Ligands AssociatedTherewith”, filed Feb. 8, 2008; and (4) International Application No.PCT/US2008/065650, entitled “Modulation of Chemosensory Receptors andLigands Associated Therewith”, filed Jun. 3, 2008; (5) U.S. ProvisionalApplication Ser. No. 61/320,528, entitled “SWEET FLAVOR MODIFIER”, filedApr. 2, 2010; and (6) U.S. patent application Ser. No. 13/076,632,entitled “SWEET FLAVOR MODIFIER”, filed Mar. 31, 2011. The content ofthese applications are herein incorporated by reference in theirentirety for all purposes.

The present invention provides methods of stabilizing sweet enhancersand compositions containing stabilized sweet enhancers.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a liquid compositioncomprising: a sweet enhancer having structural formula (I) or (II), or asalt or solvate thereof; and a photostabilizer, or a salt or solvatethereof;

wherein the sweet enhancer having structural formula (I):

wherein:

A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R₂, —NR¹CO₂R², —NR¹C(O)NR²R³,—NR¹C(S)NR²R³ or —NR¹C(═NH)NR²R³;

B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR⁴, —S(O)_(a)R⁴,—NR⁴R⁵, —C(O)NR⁴R⁵, —CO₂R⁴, —NR⁴CO₂R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴C(S)NR⁵R⁶,—NR⁴C(═NH)NR⁵R⁶, —SO₂NR⁴R⁵, —NR⁴SO₂R⁵, —NR⁴SO₂NR⁵R⁶, —B(OR⁴)(OR⁵),—P(O)(OR⁴)(OR⁵), or —P(O)(R⁴)(OR⁵);

C is —OR⁷, —S(O)_(b)R⁷, SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹,—B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR), —P(O)(R⁷)(OR), or heteroaryl;

a and b are independently 0, 1 or 2; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively, R¹ and R², R² and R³, R⁴ and R⁵, R⁵and R⁶, R⁷ and R⁸, or R⁸ and R⁹, together with the atoms to which theyare bonded, form a cycloheteroalkyl or substituted cycloheteroalkylring;

H is —C(R²¹)— or —N—;

I is —C(R²²) or —N—;

J is —C(R²³)— or —N—;

K is —C(R²⁴)— or —N—;

R²¹ is hydrogen, alkyl, substituted alkyl, halo, —CN, —OR²⁵;

R²² is hydrogen, alkyl, substituted alkyl, halo, —CN, —OR²⁷;

R²³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR²⁹,—S(O)_(f)R²⁹, —OC(O)R²⁹, —NR²⁹R³⁰, —C(O)NR²⁹R³⁰, —CO₂R²⁹, —SO₂NR²⁹R³⁰,—NR²⁹SO₂R³⁰, —B(OR²⁹)(OR³⁰), —P(O)(OR²⁹)(OR³⁰) or —P(O)(R²⁹)(OR³⁰);

R²⁴ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR³¹,—S(O)_(g)R³¹, —OC(O)R³¹, —NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹, —CO₂R³¹,—SO₂NR³¹R³², —NR³¹SO₂R³², —B(OR³¹)(OR³²), —P(O)(OR³¹)(OR³²) or—P(O)(R³¹)(OR³²); or alternatively R²³ and R²⁴, taken together with theatom to which they are attached, form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring;

f and g are independently 0, 1 or 2; and

R²⁵, R²⁷, R²⁹, R³⁰, R³¹, and R³² are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; or alternatively R²⁵ and R²⁷, R²⁷ and R²⁹, R²⁹ and R³⁰,R²⁹ and R³¹, or R³¹ and R³², together with the atoms to which they areattached, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the proviso that at most, two of H, I, J and K are —N—;

the sweet enhancer having structural formula (II):

wherein,

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR⁹, —NO₂,—S(O)_(c)R⁹, —NOR⁹, —NHOR⁹, —NR⁹COR¹⁰, —NR⁹R¹⁰, —CONR⁹R¹⁰, —CO₂R⁹ or—NR⁹CO₂R¹⁰;

R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substitutedarylalkyl;

X¹ is —CH₂—, —O—, —NR⁹—, —S—, —S(O)—, or —S(O)₂—;

X² is alkylene, substituted alkylene, heteroalkylene, or substitutedheteroalkylene;

m is 0 or 1;

Y¹ is heteroaryl, substituted heteroaryl, cycloheteroalkyl, substitutedcycloheteroalkyl, or

X³ and X⁵ are independently a covalent bond, —O— or —NR⁹—;

X⁴ is O, NR⁹, N—OR⁹, or S;

R^(x) is halo, —NO₂, —CN, —OH, —NH₂, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl;

n is 0, 1, 2, or 3;

R^(y) is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl, —NR⁹R¹⁰; and

each R⁹ and R¹⁰ is independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl;

-   -   with the proviso that when X¹ is —O— or —S—, and m is zero; then        X³ is not —O—.

In another embodiment, the present invention provides a method ofimproving stability of a sweet enhancer having structural formula (I) or(II) in a liquid composition comprising: contacting a photostabilizerwith the sweet enhancer in the liquid composition, wherein thephotostabilizer is selected from the group consisting of a chromonederivative, a coumarine derivative, a phenylpropenioc carbonyl compound,and a combination thereof.

In another embodiment, the present invention provides a method ofreducing degradation of a sweet enhancer having structural formula (I)or (II) in a liquid composition comprising: contacting a photostabilizerwith the sweet enhancer in the liquid composition, wherein thephotostabilizer is selected from the group consisting of a chromonederivative, a coumarine derivative, a phenylpropenioc carbonyl compound,and a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the photostability of Compound A (25 ppm) invarious mediums.

FIG. 2 is a graph showing the stabilization of Compound A by twophotostabilizers, respectively.

FIG. 3 is a graph showing the stabilization of Compound B by twophotostabilizers, respectively.

FIG. 4 shows the chemical structures of certain exemplary antioxidantsthat are suitable to be used as photostabilizers. Some of theseantioxidants are FEMA GRAS compounds.

FIG. 5 is a graph showing the photostability of Compound A in thepresence of various antioxidant photostabilizers.

FIG. 6A is a graph showing the photostability of Compound C in thepresence of EMIQ.

FIG. 6B is a graph showing the photostability of Compound D in thepresence of EMIQ.

FIG. 7 shows the chemical structures of some naturally occurringcinnamic acid and coumarin derivatives.

FIG. 8 is a graph showing the photostability of Compound A in thepresence of certain antioxidant photostabilizers.

FIG. 9 is a graph showing the photostability of Compound C in thepresence of Daphnetin.

FIG. 10 is a graph showing the photostability of Compound E in thepresence of EMIQ or Chlorogenic Acid.

DETAILED DESCRIPTION OF THE INVENTION

These and other embodiments, advantages, and features of the presentinvention are provided in the sections below. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

Definitions

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterms “a” and “an” are used interchangeable with “one or more” or “atleast one”. The term “or” or “and/or” is used as a function word toindicate that two words or expressions are to be taken together orindividually. The terms “comprising”, “having”, “including”, and“containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to”). The endpoints of all ranges directedto the same component or property are inclusive and independentlycombinable.

“Alkyl,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. The term“alkyl” includes “cycloalkyl” as defined hereinbelow. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Theterm “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 12 carbon atoms (C₁-C₁₂alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl). It is noted that when an alkyl group isfurther connected to another atom, it becomes an “alkylene” group. Inother words, the term “alkylene” refers to a divalent alkyl. Forexample, —CH₂CH₃ is an ethyl, while —CH₂CH₂— is an ethylene. That is,“Alkylene,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon radical derived by the removal of two hydrogen atoms from asingle carbon atom or two different carbon atoms of a parent alkane,alkene or alkyne. The term “alkylene” includes “cycloalkylene” asdefined hereinbelow. The term “alkylene” is specifically intended toinclude groups having any degree or level of saturation, i.e., groupshaving exclusively single carbon-carbon bonds, groups having one or moredouble carbon-carbon bonds, groups having one or more triplecarbon-carbon bonds and groups having mixtures of single, double andtriple carbon-carbon bonds. Where a specific level of saturation isintended, the expressions “alkanylene,” “alkenylene,” and “alkynylene”are used. In some embodiments, an alkylene group comprises from 1 to 20carbon atoms (C₁-C₂₀ alkylene). In other embodiments, an alkylene groupcomprises from 1 to 12 carbon atoms (C₁-C₂ alkylene). In still otherembodiments, an alkylene group comprises from 1 to 6 carbon atoms (C₁-C₆alkylene).

“Alkanyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. The term “alkanyl” includes “cycloakanyl” as definedhereinbelow. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The term“alkenyl” includes “cycloalkenyl” as defined hereinbelow. The group maybe in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. “Alkoxy,” by itself oras part of another substituent, refers to a radical of the formula—O—R¹⁹⁹, where R¹⁹⁹ is alkyl or substituted alkyl as defined herein.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R²⁰⁰, where R²⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 15 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. Typical arylalkyl groups include,but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyland/or arylalkynyl is used. In some embodiments, an arylalkyl group is(C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈)alkyl and the aryl moiety is (C₆-C₁₂) aryl. In still other embodiments,an arylalkyl group is (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₆-C₁₀) aryl.

“Cycloalkyl,” by itself or as part of another substituent, refers to asaturated or unsaturated cyclic alkyl radical, as defined herein.Similarly, “Cycloalkylene,” by itself or as part of another substituent,refers to a saturated or unsaturated cyclic alkylene radical, as definedherein. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl”, “cycloalkenyl”, or “cycloalkynyl” is used.Typical cycloalkyl groups include, but are not limited to, groupsderived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, andthe like. In some embodiments, the cycloalkyl group comprises from 3 to10 ring atoms (C₃-C₁₀ cycloalkyl). In other embodiments, the cycloalkylgroup comprises from 3 to 7 ring atoms (C₃-C₇ cycloalkyl). Thecycloalkyl may be further substituted by one or more heteroatomsincluding, but not limited to, N, P, O, S, and Si, which attach to thecarbon atoms of the cycloalkyl via monovalent or multivalent bond.

“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” bythemselves or as part of other substituents, refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and optionally any associated hydrogen atoms), are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Similarly, “Heteroalkylene,”“Heteroalkanylene,” “Heteroalkenylene” and “Heteroalkynylene,” bythemselves or as part of other substituents, refer to alkylene,alkanylene, alkenylene and alkynyenel groups, respectively, in which oneor more of the carbon atoms (and optionally any associated hydrogenatoms), are each, independently of one another, replaced with the sameor different heteroatoms or heteroatomic groups. Typical heteroatoms orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—,—S(O)₂NH— and the like and combinations thereof. The heteroatoms orheteroatomic groups may be placed at any interior position of the alkyl,alkenyl or alkynyl groups. Typical heteroatomic groups which can beincluded in these groups include, but are not limited to, —O—, —S—,—O—O—, —S—S—, —O—S—, —NR²⁰¹R²⁰²—, ═N—N═, —N═N—, —N═N—NR²⁰³R²⁰⁴, —PR²⁰⁵—,—P(O)₂—, —POR²⁰⁶—, —O—P(O)₂—, —SO—, —SO₂—, —SnR²⁰⁷R²⁰⁸— and the like,where R²⁰¹, R²⁰², R²⁰³, R²⁰⁴, R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Cycloheteroalkyl,” or “Heterocyclyl,” by itself or as part of anothersubstituent, refers to a saturated or unsaturated cyclic alkyl radicalin which one or more carbon atoms (and optionally any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Similarly, “Cycloheteroalkylene,” by itself or as part ofanother substituent, refers to a saturated or unsaturated cyclicalkylene radical in which one or more carbon atoms (and optionally anyassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatom. The cycloheteroalkyl may be further substituted byone or more heteroatoms including, but not limited to, N, P, O, S, andSi, which attach to the carbon atoms of the cycloheteroalkyl viamonovalent or multivalent bond. Typical heteroatoms to replace thecarbon atom(s) include, but are not limited to, N, P, O, S, Si, etc.Where a specific level of saturation is intended, the nomenclature“cycloheteroalkanyl” or “cycloheteroalkenyl” is used. Typicalcycloheteroalkyl groups include, but are not limited to, groups derivedfrom epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and thelike. In some embodiments, the cycloheteroalkyl group comprises from 3to 10 ring atoms (3-10 membered cycloheteroalkyl) In other embodiments,the cycloalkyl group comprise from 5 to 7 ring atoms (5-7 memberedcycloheteroalkyl). A cycloheteroalkyl group may be substituted at aheteroatom, for example, a nitrogen atom, with a (C₁-C₆) alkyl group. Asspecific examples, N-methyl-imidazolidinyl, N-methyl-morpholinyl,N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl andN-methyl-pyrrolidinyl are included within the definition of“cycloheteroalkyl.” A cycloheteroalkyl group may be attached to theremainder of the molecule via a ring carbon atom or a ring heteroatom.

The term “present compound(s)”, “compound(s) of the present invention”,or “sweet enhancer(s)” as used herein refers to compounds encompassed bystructural formulae disclosed herein, e.g., formula (I), (Ia), and (II),and includes any specific compounds within these formulae whosestructure is disclosed herein. Compounds may be identified either bytheir chemical structure and/or chemical name. When the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the identity of the compound. The compounds describedherein may contain one or more chiral centers and/or double bonds andtherefore, may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers or diastereomers. Accordingly,the chemical structures depicted herein encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures can be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan. Thecompounds may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The term “tautomer” as used herein refers toisomers that change into one another with great ease so that they canexist together in equilibrium. In general, compounds may be hydrated,solvated or N-oxides. Certain compounds may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated herein and are intended to bewithin the scope of the present invention. Further, it should beunderstood, when partial structures of the compounds are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule.

“Halo,” by itself or as part of another substituent refers to a radical—F, —Cl, —Br or —I.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, P3-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Solvate” means a compound formed by solvation (the combination ofsolvent molecules with molecules or ions of the solute), or an aggregatethat consists of a solute ion or molecule, i.e., a compound of thepresent invention, with one or more solvent molecules. When water is thesolvent, the corresponding solvate is “hydrate”.

“N-oxide”, also known as amine oxide or amine-N-oxide, means a compoundthat derives from a compound of the present invention via oxidation ofan amine group of the compound of the present invention. An N-oxidetypically contains the functional group R₃N⁺—O⁻ (sometimes written asR₃N═O or R₃N→O).

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O—, ═O, —OR^(b), —SR^(b), —S⁻, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O—, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O—),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O—,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s may be taken together with the nitrogenatom to which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(C)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl. As another specificexample, a substituted alkyl is meant to include -alkylene-O-alkyl,-alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(O)OR^(b),-alkylene-C(O)NR^(b)R^(b), and —CH₂—CH₂—C(O)—CH₃. The one or moresubstituent groups, taken together with the atoms to which they arebonded, may form a cyclic ring including cycloalkyl andcycloheteroalkyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl,—CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O—, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined. Substituent groups from theabove lists useful for substituting other specified groups or atoms willbe apparent to those of skill in the art.

The substituents used to substitute a specified group can be furthersubstituted, typically with one or more of the same or different groupsselected from the various groups specified above.

“Sugar ring” includes any ring structure formed by a monosaccharide, adisaccharide, an oligosaccharide, a polysaccharide, a sugar acid, asugar alcohol, or a reducing sugar.

“Vehicle” refers to a diluent, adjuvant, excipient or carrier with whicha compound is administered.

As used herein, an “ingestible composition” includes any substance that,either alone or together with another substance, can be taken by mouthwhether intended for consumption or not. The ingestible compositionincludes both “food or beverage products” and “non-edible products”. By“Food or beverage products”, it is meant any edible product intended forconsumption by humans or animals, including solids, semi-solids, orliquids (e.g., beverages). The term “non-edible products” or“noncomestible composition” includes supplements, nutraceuticals,functional food products (e.g., any fresh or processed food claimed tohave a health-promoting and/or disease-preventing properties beyond thebasic nutritional function of supplying nutrients), pharmaceutical andover the counter medications, oral care products such as dentifrices andmouthwashes, cosmetic products such as sweetened lip balms and otherpersonal care products that use sucralose and or other sweeteners.

A “ingestibly acceptable carrier or excipient” is a solid or liquidmedium and/or composition that is used to prepare a desired disperseddosage form of the inventive compound, in order to administer theinventive compound in a dispersed/diluted form, so that the biologicaleffectiveness of the inventive compound is maximized. Ingestiblyacceptable carriers includes many common food ingredients, such as waterat neutral, acidic, or basic pH, fruit or vegetable juices, vinegar,marinades, beer, wine, natural water/fat emulsions such as milk orcondensed milk, edible oils and shortenings, fatty acids and their alkylesters, low molecular weight oligomers of propylene glycol, glycerylesters of fatty acids, and dispersions or emulsions of such hydrophobicsubstances in aqueous media, salts such as sodium chloride, wheatflours, solvents such as ethanol, solid edible diluents such asvegetable powders or flours, or other liquid vehicles; dispersion orsuspension aids; surface active agents; isotonic agents; thickening oremulsifying agents, preservatives; solid binders; lubricants and thelike.

An “enhancer” herein refers to a compound that modulates (increases) theactivation of a particular receptor, preferably the chemosensory, e.g.,T1R2/T1R3 receptor but which by itself does not result in substantialactivation of the particular receptor. Herein such enhancers willenhance the activation of a chemosensory receptor by its ligand.Typically the “enhancer” will be specific to a particular ligand, i.e.,it will not enhance the activation of a chemosensory receptor bychemosensory ligands other than the particular chemosensory ligand orligands closely related thereto.

A “flavor” herein refers to the perception of taste in a subject, whichinclude sweet, sour, salty, bitter and umami. The subject may be a humanor an animal.

A “flavoring agent” herein refers to a compound or a biologicallyacceptable salt or solvate thereof that induces a flavor or taste in ananimal or a human.

A “flavor modifier” herein refers to a compound or biologicallyacceptable salt or solvate thereof that modulates, including enhancingor potentiating, and inducing, the tastes of a natural or syntheticflavoring agent in an animal or a human.

A “flavor enhancer” herein refers to a compound or biologicallyacceptable salt thereof that enhances and/or multiplies the tastes of anatural or synthetic flavoring agent, or a comestible compositioncomprising the flavor enhancer.

A “sweet flavor” refers to the sweet taste typically induced by sugar,such as sucrose, in an animal or a human.

A “sweet flavoring agent”, “sweet flavor entity”, “sweetener”, “sweetcompound”, or “sweet receptor activating compound” herein refers to acompound or biologically acceptable salt thereof that elicits adetectable sweet flavor in a subject, e.g., sucrose or a compound thatactivates a T1R2/T1R3 receptor in vitro. The subject may be a human oran animal.

A “sweet flavor modifier” herein refers to a compound or biologicallyacceptable salt or solvate thereof that modulates, including enhancingor potentiating, inducing, and blocking, the sweet taste of a natural orsynthetic sweet flavoring agents in an animal or a human.

A “sweet flavor enhancer” herein refers to a compound or biologicallyacceptable salt thereof that enhances or potentiates the sweet taste ofa natural or synthetic sweet flavoring agents in an animal or a human.

A “sweet receptor activating compound” herein refers to a compound thatactivates a sweet receptor, such as a T1R2/T1R3 receptor.

A “sweet receptor modulating compound” herein refers to a compound thatmodulates (activates, enhances or blocks) a sweet receptor such as aT1R2/T1R3 receptor.

A “sweet receptor enhancing compound” herein refers to a compound thatenhances or potentiates the effect of a natural or synthetic sweetreceptor activating compound, e.g., sucrose.

A “sweet flavor enhancing amount” herein refers to an amount of acompound that is sufficient to enhance the taste of a natural orsynthetic flavoring agents, e.g., sucrose or sucralose, in a ingestiblecomposition, as perceived by an animal or a human. A broad range of asweet flavor enhancing amount can be from about 0.001 ppm to 100 ppm, ora narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges ofsweet flavor enhancing amounts can be from about 0.01 ppm to about 30ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5ppm, or from about 0.1 ppm to about 3 ppm.

A “photostabilizer” refers to a compound which can stabilize a sweetenhancer under light exposure. That is, the photostabilizer can improve,increase, or enhance the photostability of a sweet enhancer or decreaseor reduce degradation of a sweet enhancer when exposed to a lightsource. The light source can be artificial, such as ultraviolet (UV)lamp, or natural, such as sunlight. The present photostabilizers mayexert their photostabilizing capability via a wide range of mechanism.In other words, the present photostabilizers are not limited to anyparticular stabilization mechanism. In one embodiment, the degradationof the sweet enhancer is caused by photo-oxidation, then thephotostabilizers may be antioxidants.

A “sweet enhancer stabilizing amount” refers to an amount orconcentration of the photostabilizer that is sufficient to substantiallyreduce, decrease, lessen, or prevent the degradation of a sweet enhancerunder light exposure. Depending on the amount and/or concentration ofthe sweet enhancer in a given composition, the sweet enhancerstabilizing amount may vary with a wide range. In one embodiment, thephotostabilizer is present in a sweet enhancer-containing composition inan amount ranging from about 10 ppm to about 500 ppm. In one embodiment,the photostabilizer is present in a sweet enhancer-containingcomposition in an amount ranging from about 50 ppm to about 300 ppm. Inanother embodiment, the photostabilizer is present in a sweetenhancer-containing composition in an amount ranging from about 100 ppmto about 200 ppm.

A “liquid composition” refers to a composition that is not completelysolid. The liquid composition can be a ingestible composition or anon-ingestible composition. For example, the liquid composition can bein form of a solution, suspension, oil, gel, paste, porridge, or mixturethereof. The liquid composition may also be a food or beverage product,a pharmaceutical composition, a nutritional product, a dietarysupplement, over-the-counter medication, or oral care product.

Compounds of Formula (I)

In one embodiment, the sweet enhancers of the present invention havestructural Formula (I) or (I′), or a tautomer, salt, and/or solvatethereof:

or a tautomer, salt, and/or solvate thereof, wherein:

A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R², —NR¹C(O)NR²R³,—NR¹C(S)NR²R³ or —NR¹C(═NH)NR²R³;

B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR⁴, —S(O)_(a)R⁴,—NR⁴R⁵, —C(O)NR⁴R⁵, —CO₂R⁴, —NR⁴CO₂R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴C(S)NR⁵R⁶,—NR⁴C(═NH)NR⁵R⁶, —SO₂NR⁴R⁵, —NR⁴SO₂R⁵, —NR⁴SO₂NR⁵R⁶, —B(OR⁴)(OR⁵),—P(O)(OR⁴)(OR⁵), or —P(O)(R⁴)(OR⁵);

C is —OR⁷, —S(O)_(b)R⁷, SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R,—NR⁷C(O)NR⁸R⁹, —NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R, —NR⁷SO₂R, —NR⁷SO₂NR⁸R⁹,—B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), —P(O)(R⁷)(OR⁸), or heteroaryl (forexample, tetrazole);

D is an aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring wherein the ring is optionally fused to anotheraryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring;

a and b are independently 0, 1 or 2;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R, and R⁹ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively, R¹ and R², R² and R³, R⁴ and R⁵, R⁵and R⁶, R⁷ and R⁸, or R⁸ and R⁹, together with the atoms to which theyare bonded, form a cycloheteroalkyl or substituted cycloheteroalkylring;

H is —C(R²¹)— or —N—;

I is —C(R²²) or —N—;

J is —C(R²³)— or —N—;

K is —C(R²⁴)— or —N—;

R²¹ is hydrogen, alkyl, substituted alkyl, halo, —CN, —OR²⁵;

R²² is hydrogen, alkyl, substituted alkyl, halo, —CN, —OR²⁷;

R²³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR²⁹,—S(O)_(f)R²⁹, —OC(O)R²⁹, —NR²⁹R³⁰, —C(O)NR²⁹R³⁰, —CO₂R²⁹, —SO₂NR²⁹R³⁰,—NR²⁹SO₂R³⁰, —B(OR²⁹)(OR³⁰), —P(O)(OR²⁹)(OR³⁰) or —P(O)(R²⁹)(OR³⁰);

R²⁴ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR³¹,—S(O)_(g)R³¹, —OC(O)R³¹, —NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹, —CO₂R³¹,—SO₂NR³¹R³², —NR³¹SO₂R³², —B(OR³¹)(OR³²), —P(O)(OR³¹)(OR³²) or—P(O)(R³¹)(OR³²); or alternatively R²³ and R²⁴, taken together with theatom to which they are attached, form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring;

f and g are independently 0, 1 or 2; and

R²⁵, R²⁷, R²⁹, R³⁰, R³¹, and R³² are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; or alternatively R²⁵ and R²⁷, R²⁷ and R²⁹, R²⁹ and R³⁰,R²⁹ and R³¹, or R³¹ and R³², together with the atoms to which they areattached, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the proviso that at most, two of H, I, J and K are —N—.

In one embodiment of Formula (I) or (I′), one or two of H, I, J and Kare —N—.

In one embodiment of Formula (I) or (I′), H is —N—, I is —C(R²²)—, J is—C(R²³)—, and K is —C(R²⁴)—.

In one embodiment of Formula (I) or (I′), H is —C(R²¹)—, I is —N—, J is—C(R²³)—, and K is —C(R²⁴)—.

In one embodiment of Formula (I) or (I′), H is —C(R²¹)—, I is —C(R²²)—,J is —N—, and K is —C(R²⁴)—.

In one embodiment of Formula (I) or (I′), H is —C(R²¹)—, I is —C(R²²), Jis —C(R²³)—, and K is —N—.

In one embodiment of Formula (I) or (I′), H and I are —N—.

In one embodiment of Formula (I) or (I′), H and J are —N—.

In one embodiment of Formula (I) or (I′), H and K are —N—.

In one embodiment of Formula (I) or (I′), I and J are —N—.

In one embodiment of Formula (I) or (I′), I and K are —N—.

In one embodiment of Formula (I) or (I′), J and K are —N—.

In one embodiment of the present invention, the compounds of Formula (I)have a structural Formula (Ia) or (I′a),

or a tautomer, salt, and/or solvate thereof.

In one embodiment of Formula (Ia) or (I′a), two or three of R²¹, R²²,R²³, and R²⁴ are hydrogen.

In one embodiment of Formula (Ia) or (I′a), R²¹ is hydrogen; R²² ishydrogen, alkyl, substituted alkyl, halo, —CN, or —OR²⁷; R²³ ishydrogen, alkyl, substituted alkyl, —CN, —OR²⁹, —S(O)_(f)R²⁹, —OC(O)R²⁹,—NR²⁹R³⁰, —C(O)NR²⁹R³⁰, —C(O)R²⁹, —CO₂R²⁹, —SO₂NR²⁹R³⁰, or —NR²⁹SO₂R³⁰;R²⁴ is hydrogen, alkyl, substituted alkyl, —CN, —OR³¹, —S(O)_(g)R³¹,—OC(O)R³¹, —NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹, —CO₂R³¹, —SO₂NR³¹R³², or—NR³¹SO₂R³²; or alternatively R²³ and R²⁴, taken together with the atomsto which they are attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring; and R²⁷, R²⁹,R³⁰, R³¹, and R³² are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;or alternatively R²⁵ and R²⁷, R²⁷ and R²⁹, R²⁹ and R³⁰, R²⁹ and R³¹, orR³¹ and R³², together with the atoms to which they are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of Formula (Ia) or (I′a), R²¹ and R²² are allhydrogen.

In one embodiment of Formula (Ia) or (I′a), R²³ and R²⁴, taken togetherwith the atom to which they are attached, form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring.

In one embodiment of Formula (Ia) or (I′a), R²³ and R²⁴, taken togetherwith the atom to which they are attached, form a substitutedcycloheteroalkyl ring containing one or more substituents selected fromthe group consisting of —R^(a), halo, —O—, ═O, —OR^(b), —SR^(b), —S—,═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O—,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O—, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(O)OR^(b),—C(S)R^(b), —C(NR^(b))R^(b), —C(O)O—, —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) isselected from the group consisting of alkyl, cycloalkyl, heteroalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; eachR^(b) is independently hydrogen or R^(a); and each R^(c) isindependently R^(b) or alternatively, the two R^(c)s may be takentogether with the nitrogen atom to which they are bonded form a 4-, 5-,6- or 7-membered cycloheteroalkyl which may optionally include from 1 to4 of the same or different additional heteroatoms selected from thegroup consisting of O, N and S; or alternatively, two of thesubstituents on the cycloheteroalkyl ring, together with the atoms towhich they are bonded, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring.

In one embodiment of Formula (Ia) or (I′a), R²¹, R²², R²³, and R²⁴ areall hydrogen.

In one embodiment of Formula (Ia) or (I′a), A is —OR¹, —NR¹C(O)R²,—NHOR¹, —NR¹R², —NOR¹, —NR¹CO₂R², —NR¹C(O)NR²R³, —NR¹CSNR²R³, or—NR¹C(═NH)NR²R³.

In one embodiment of Formula (Ia) or (I′a), C is —S(O)_(b)R⁷, SO₃R⁷,—C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(S)NR⁸R⁹,—NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸),—P(O)(OR⁷)(OR⁸), or —P(O)(R⁷)(OR⁸).

In one embodiment of Formula (Ia) or (I′a), B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of Formula (Ia) or (I′a), three of R²¹, R²², R²³, andR²⁴ are hydrogen; A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R²,—NR¹C(O)NR²R³, —NR¹C(S)NR²R³, or —NR¹C(═NH)NR²R³; C is —S(O)_(b)R⁷,SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(S)NR⁸R⁹,—NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸),—P(O)(OR⁷)(OR⁸), or —P(O)(R⁷)(OR⁸) or tetrazole; B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of the present invention, the compounds of Formula(Ia) or (I′a) have a structural Formula (Ib) or (I′b),

or a tautomer, salt, and/or solvate thereof; wherein

L¹ is alkylene or substituted alkylene;

L² is —NR³⁴—, —O—, —S—, —NR³⁴—C(O)—, —C(O)—NR³⁴—, —O—C(O)—, —C(O)—O—,—NR³⁴—C(O)—O—, —O—C(O)—NR³⁴—, —NR³⁴—C(O)—NR³⁵—, —O—C(O)—O—,-hetercyclylene-C(O)—, or -(substituted hetercyclylene)-C(O)—;

R³³ is alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl;aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; and

R³⁴ and R³⁵ are independently hydrogen, alkyl, substituted alkyl,carbocyclyl, substituted carbocyclyl; aryl, substituted aryl, arylalkyl,substituted arylalkyl, heterocyclyl, substituted heterocyclyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

In one embodiment of the present invention, the compounds of Formula(Ia) or (I′a) have a structural Formula (Ic), (I′c), (Id), or (I′d),

or a tautomer, salt, and/or solvate thereof; wherein R³³ is alkyl,substituted alkyl, carbocyclyl, substituted carbocyclyl; aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of Formula (Ic), (I′c), (Id) or (I′d), R³³ is alkyl,substituted alkyl, carbocyclyl, substituted carbocyclyl; heterocyclyl,substituted heterocyclyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment of Formula (Ib), (Ic), or (Id), A is —OR¹, —NR¹C(O)R²,—NHOR¹, —NR¹R², —NR¹CO₂R², —NR¹C(O)NR²R³, —NR¹CSNR²R³, or—NR¹C(═NH)NR²R³.

In one embodiment of Formula (Ib), (Ic), or (Id), C is —S(O)_(b)R⁷,SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R, —NR⁷C(O)NR⁸R⁹, —NR⁷C(S)NR⁸R⁹,—NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R, —NR⁷SO₂R, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR),—P(O)(OR⁷)(OR), or —P(O)(R⁷)(OR⁸).

In one embodiment of Formula (Ib), (Ic), or (Id), B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of Formula (Ib), A is —OR¹, —NHOR¹, or —NR¹R²; B ishydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; C is—SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —SO₂NR⁷R⁸, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR), or—P(O)(R⁷)(OR⁸); L¹ is alkylene or substituted alkylene; L² is —NR³⁴—,—O—, —NR³⁴—C(O)—, —C(O)—NR³⁴—, —O—C(O)—, —C(O)—O—,-hetercyclylene-C(O)—, or -(substituted hetercyclylene)-C(O)—; R³³ isalkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl; aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; and R³⁴ and R³⁵ are independently hydrogen, alkyl, orsubstituted alkyl.

In one embodiment of Formula (Ic) or (Id), A is —OR¹, —NHOR¹, or —NR¹R²;B is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; C is—SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —SO₂NR⁷R⁸, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), or—P(O)(R⁷)(OR⁸); R³³ is alkyl, substituted alkyl, carbocyclyl,substituted carbocyclyl; heterocyclyl, substituted heterocyclyl,heteroalkyl, or substituted heteroalkyl.

In one embodiment, the compound of Formula (Ia) can be represented bystructural Formula (Ie):

or a salt and/or solvate thereof; wherein

R¹ and R² are independently hydrogen or C₁ to C₆ alkyl;

L is C₁ to C₁₂ alkylene or substituted C₁ to C₁₂ alkylene;

M is —NR⁴—C(O)— or —C(O)—NR⁴—;

R⁴ is hydrogen or C₁ to C₆ alkyl; or alternatively, when M is—NR⁴—C(O)—, R⁴ and one or more atoms of L, together with the nitrogen towhich they are attached, form a 5- to 8-membered heterocyclic ring whichis optionally substituted and contains one to three heteroatoms selectedfrom nitrogen, oxygen, and sulfur; and

R³ is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-memberedheterocyclyl, or substituted 5- to 8-membered heterocyclyl; oralternatively, when M is —C(O)—NR⁴—, R⁴ and one or more atoms of R³,together with the nitrogen to which they are attached, form a 5- to8-membered heterocyclic ring which is optionally substituted andcontains one to three heteroatoms selected from nitrogen, oxygen, andsulfur.

In one embodiment of Formula (Ie), the substituent group(s) on the C1 toC12 alkylene, the heterocyclyl, the heterocyclic ring, and the C1 to C12alkyl is selected from the group consisting of halo, amino, N-alkylamino, N,N-dialkyl amino, hydroxyl, alkoxy, aryl, heteroaryl,heterocyclyl, carbocyclyl, ═O, ═S, ═NR^(a), ═N—OR^(a), —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —C(O)R^(b), —C(O)OR^(a), —C(O)NR^(a)R^(a),—OC(O)OH, —OC(O)OR^(a), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(a), and—NR^(a)C(O)NR^(a)R^(a), wherein each R^(a) is independently hydrogen oralkyl including straight, branched, and cyclic alkyl; or alternatively,two R^(a), taken together with the nitrogen to which they are attached,form a heterocyclic ring; and each R^(b) is alkyl including straight,branched, and cyclic alkyl.

In one embodiment of Formula (Ie), R¹ and R² are both hydrogen.

In one embodiment of Formula (Ie), the alkylene is straight, branched,cyclic, or a combination thereof.

In one embodiment of Formula (Ie), the alkyl is straight, branched,cyclic, or a combination thereof.

In one embodiment of Formula (Ie), the compound can be represented bystructural Formula (IeA):

wherein,

L is C1 to C12 alkylene or substituted C1 to C12 alkylene;

R⁴ is hydrogen or C1 to C6 alkyl; or alternatively, R⁴ and one or moreatoms of L, together with the nitrogen to which they are attached, forma 5- to 8-membered heterocyclic ring which is optionally substituted andcontains one to three heteroatoms selected from nitrogen, oxygen, andsulfur; and

R³ is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-memberedheterocyclyl, or substituted 5- to 8-membered heterocyclyl.

In one embodiment of Formula (IeA), L is branched or cyclic C3 to C6alkylene; R⁴ is hydrogen; and R³ is branched C3 to C6 alkyl or straightC1 to C6 alkyl.

In one embodiment of Formula (I), the compound can be represented bystructural Formula (IeB):

wherein:

L is C1 to C12 alkylene or substituted C1 to C12 alkylene;

R⁴ is hydrogen or C1 to C6 alkyl; and

R³ is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-memberedheterocyclyl, substituted 5- to 8-membered heterocyclyl; oralternatively, R⁴ and one or more atoms of R³, together with thenitrogen to which they are attached, form a 5- to 8-memberedheterocyclic ring which is optionally substituted and contains one tothree heteroatoms selected from nitrogen, oxygen, and sulfur.

In one embodiment of Formula (IeB), L is straight C1 to C6 alkylene orbranched C3 to C6 alkylene; R⁴ is hydrogen; and R³ is straight C1 to C6alkyl or branched or cyclic C3 to C6 alkyl.

In some specific embodiments, the sweet enhancer having structuralformula (I) or (I′) is selected from the group consisting of

or a tautomer, salt, solvate, and/or ester thereof.

Compounds of Formula (II)

In one embodiment, the present invention provides a compound havingstructural Formula (II), or a tautomer, salt or solvate thereof:

wherein,

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR⁹, —NO₂,—S(O)_(c)R⁹, —NOR⁹, —NHOR⁹, —NR⁹COR¹⁰, —NR⁹R¹⁰, —CONR⁹R¹⁰, —CO₂R⁹ or—NR⁹CO₂R¹⁰;

R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substitutedarylalkyl;

X¹ is —CH₂—, —O—, —NR⁹—, —S—, —S(O)—, or —S(O)₂—;

X² is alkylene, substituted alkylene, heteroalkylene, or substitutedheteroalkylene;

m is 0 or 1;

Y¹ is heteroaryl, substituted heteroaryl, cycloheteroalkyl, substitutedcycloheteroalkyl, or

X³ and X⁵ are independently a covalent bond, —O— or —NR⁹—;

X⁴ is O, NR⁹, N—OR⁹, or S;

R^(x) is halo, —NO₂, —CN, —OH, —NH₂, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl;

n is 0, 1, 2, or 3;

R^(y) is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl, —NR⁹R¹⁰; and

each R⁹ and R¹⁰ is independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl;

with the proviso that when X¹ is —O— or —S—, and m is zero; then X³ isnot —O—.

In one embodiment of Formula (II), X¹ is —CH₂—; and Y¹ is

In one embodiment of Formula (II), X¹ is —O—, —NR⁹—, or —S—; m is 0 or1, and Y¹ is cycloheteroalkyl or substituted cycloheteroalkyl.

In one embodiment of Formula (II), X¹ is —O—, —NR⁹—, or —S—; m is 1, andY¹ is

In some embodiments of Formula (II), X² is alkanylene, substitutedalkanylene, heteroalkanylene, substituted heteroalkanylene, alkenylene,substituted alkenylene, heteroalkenylene, or substitutedheteroalkenylene.

In some embodiments of Formula (II), X² is methylene, ethylene,propylene, iso-propylene, butylene, iso-butylene, sec-butylene,pentylene, hexylene, heptylene, dimethylethylene, methylcyclopropylene,cyclopropylmethylene, ethenylene, propenylene, or butenylene.

In one embodiment of Formula (II), A is hydrogen, alkyl, substitutedalkyl, —CN, —NO₂, —OR⁹, —S(O)_(c)R⁹, —NR⁹COR¹⁰, —NHOR⁹, —NR⁹R¹⁰, —NOR⁹,—CONR⁹R¹⁰, —CO₂R⁹, —NR⁹CO₂R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CSNR¹⁰R¹¹,—NR⁹C(═NH)NR¹⁰R¹¹.

In one embodiment of Formula (II), R¹⁷ is hydrogen, alkyl, orsubstituted alkyl.

In one embodiment of Formula (II), Y¹ is cycloheteroalkanyl, substitutedcycloheteroalkanyl, cycloheteroalkenyl, or substitutedcycloheteroalkenyl. It is preferable that Y¹ is piperidinyl, substitutedpiperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl,tetrahydropyranyl, substituted tetrahydropyranyl, dihydrofuranyl,substituted dihydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl,oxetanyl, substituted oxetanyl, saccharide ring or its derivative,substituted saccharide ring or its derivative.

In one embodiment of Formula (II), Y¹ is heteroaryl or substitutedheteroaryl. It is preferable that Y¹ is pyridinyl, substitutedpyridinyl, pyrrolyl, substituted pyrrolyl, furanyl, substituted furanyl,pyrazolyl, substituted pyrazolyl, isoxazolyl, substituted isoxazolyl,oxazolyl, and substituted oxazolyl. It is also preferable that thesubstituted cycloheteroalkanyl or the substituted cycloheteroalkenylcomprises one or more substituents selected from the group consisting ofalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —CN, —OR⁹, —NO₂, —S(O)_(c)R⁹, —NOR⁹, —NHOR⁹, —NR⁹COR¹⁰,—NR⁹R¹⁰, —CONR⁹R¹⁰, —CO₂R⁹, and —NR⁹CO₂R¹⁰

In one embodiment of Formula (II), Y is

It is preferable that X⁴ is O.

In one embodiment of Formula (II), —X³—C(X⁴)—X⁵— is —C(O)—, —C(O)—NH—,—NH—C(O)—, —NH—C(O)—NH—, —C(O)—O—, —O—C(O)—, —O—C(O)—O—, —NH—C(O)—O—,—O—C(O)—NH—, —C(NH)—, —C(NH)—NH—, —NH—C(NH)—, —NH—C(NH)—NH—, —C(NH)—O—,—O—C(NH)—, —O—C(NH)—O—, —NH—C(NH)—O—, —O—C(NH)—NH—, —C(N—OH)—, or—C(S)—.

In one embodiment of Formula (II), A is hydrogen, alkyl, substitutedalkyl, or —NR⁹R¹⁰; R¹⁷ is hydrogen; and Y¹ is piperidinyl, substitutedpiperidinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl,tetrahydropyranyl, substituted tetrahydropyranyl, dihydrofuranyl,substituted dihydrofuranyl, pyrrolidinyl, substituted pyrrolidinyl,oxetanyl, substituted oxetanyl, monosaccharide ring, substitutedmonosaccharide ring, pyridinyl, substituted pyridinyl, pyrrolyl,substituted pyrrolyl, furanyl, substituted furanyl, pyrazolyl,substituted pyrazolyl, isoxazolyl, substituted isoxazolyl, oxazolyl, orsubstituted oxazolyl.

In one embodiment of Formula (II), A is hydrogen, alkyl, substitutedalkyl, or —NR⁹R¹⁰; R¹⁷ is hydrogen; Y¹ is —X³—C(X⁴)—X⁵—; and—X³—C(X⁴)—X⁵— is —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—NH—, —C(O)—O—,—O—C(O)—, —O—C(O)—O—, —NH—C(O)—O—, —O—C(O)—NH—, —C(NH)—, —C(NH)—NH—,—NH—C(NH)—, —NH—C(NH)—NH—, —C(NH)—O—, —O—C(NH)—, —O—C(NH)—O—,—NH—C(NH)—O—, —O—C(NH)—NH—, —S(O)₂—, —NH—S(O)₂—, —S(O)₂—NH—, —O—S(O)₂—,—S(O)₂—O—, —C(N—OH)— or —C(S)—.

In some specific embodiments of Formula (II), the compound hasstructural formula selected from the group consisting of

or a tautomer, salt, solvate, and/or ester thereof. In some preferredembodiments, the salt of these compounds is a hydrochloride ortrifluoroacetate salt.

Photostabilizers

Sweet enhancers may degrade when exposed to a light source (artificialand/or natural), e.g., ultraviolet (UV) radiation and/or sunlight, andthereby decreases their sweet enhancing capability and may even produceother undesirable consequences. Photostabilizers can be used tostabilize the sweet enhancers that are under light exposure.

The photostability of the present sweet enhancers will be increased whenthose sweet enhancers are used together with photostabilizers. In otherwords, the degradation of the present sweet enhancers upon exposure to alight source will be reduced when those sweet enhancers are usedtogether with photostabilizers. In one embodiment, the present inventionprovides a method of improving stability of one or more sweet enhancerin a liquid composition, wherein a photostabilizer is in contact withthe sweet enhancer, for example, the photostabilizer and the sweetenhancer co-exist in the same liquid composition. In another embodiment,the present invention provides a method of reducing degradation of oneor more sweet enhancer in a liquid composition when exposed to a lightsource, wherein a photostabilizer is in contact with the sweet enhancer,for example, the photostabilizer and the sweet enhancer co-exist in thesame liquid composition.

The photostabilizers suitable for the present invention include, but arenot limited to, antioxidants. In one embodiment, the antioxidant is aphenol-based compound, i.e., a phenol-based antioxidant. By“phenol-based compound”, it is meant an organic compound containing aphenol moiety, i.e., —C₆H₅—OH. In one embodiment, the phenol-basedantioxidant is selected from a group consisting of a dihydrochalconederivative, a flavanone derivative, a chromone derivative, a coumarinederivative, a phenylpropenioc carbonyl compound, a phenylpropanioccarbonyl compound, and a combination thereof. In another embodiment, thephenol-based antioxidant is a naturally occurring compound and/or a FEMAGRAS compound.

In one embodiment, the chromone derivative has structural formula (III):

wherein,

m is 1, 2, 3, or 4;

n is 0, 1, or 2;

each R¹ and R² are independently —R^(a), halo, —O—, ═O, —OR^(b),—SR^(b), —S—, ═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CN,—OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂₀—, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O—, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b), or —NR^(b)C(NR^(b))NR^(c)R^(c); and at least oneof R¹ is —OH;

R^(a) is selected from the group consisting of a sugar ring, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

each R^(b) is independently hydrogen or R^(a); and

each R^(c) is independently R^(b) or alternatively, the two R^(c)s maybe taken together with the nitrogen atom to which they are bonded form a4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally includefrom 1 to 4 of the same or different additional heteroatoms selectedfrom the group consisting of O, N and S.

In one embodiment, the coumarine derivative has structural formula (IV):

wherein,

m is 1, 2, 3, or 4;

n is 0, 1, or 2;

each R¹ and R² are independently —R^(a), halo, —O—, ═O, —OR^(b),—SR^(b), —S—, ═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CN,—OCN, —SCN, —NO, —N₀₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O—, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b), or —NR^(b)C(NR^(b))NR^(c)R^(c); and at least oneof R¹ is —OH;

R^(a) is selected from the group consisting of a sugar ring, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

each R^(b) is independently hydrogen or R^(a); and

each R^(c) is independently R^(b) or alternatively, the two R^(c)s maybe taken together with the nitrogen atom to which they are bonded form a4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally includefrom 1 to 4 of the same or different additional heteroatoms selectedfrom the group consisting of O, N and S.

In one embodiment, the phenylpropenioc carbonyl compound has structuralformula (V):

wherein,

m is 1, 2, 3, 4, or 5;

X is —R^(a), —O—, —OR^(b), —SR^(b), —S—, —NR^(c)R^(c), trihalomethyl,—OCN, —SCN, —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —C(O)R^(b),—C(S)R^(b), —C(NR^(b))R^(b), —C(O)O—, —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)O—, —OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b), or—NR^(b)C(NR^(b))NR^(c)R^(c),

each R¹ is independently —R^(a), halo, —O—, ═O, —OR^(b), —SR^(b), —S—,═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O—,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b), or—NR^(b)C(NR^(b))NR^(c)R^(c); and at least one of R¹ is —OH;

R^(a) is selected from the group consisting of a sugar ring, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

each R^(b) is independently hydrogen or R^(a); and

each R^(c) is independently R^(b) or alternatively, the two R^(c)s maybe taken together with the nitrogen atom to which they are bonded form a4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally includefrom 1 to 4 of the same or different additional heteroatoms selectedfrom the group consisting of O, N and S.

In one embodiment, the dihydrochalcone derivative has structural formula(VI):

wherein,

L is an optionally substituted C₁ to C₄ alkylene;

m is 1, 2, 3, 4, or 5;

n is 0, 1, 2, 3, 4, or 5;

each R¹ and R² are independently —R^(a), halo, —O—, ═O, —OR^(b),—SR^(b), —S—, ═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CN,—OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O—,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O—, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O—, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b), or —NR^(b)C(NR^(b))NR^(c)R^(c); and at least oneof R¹ and R² is —OH;

R^(a) is selected from the group consisting of a sugar ring, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

each R^(b) is independently hydrogen or R^(a); and

each R^(c) is independently R^(b) or alternatively, the two R^(c)s maybe taken together with the nitrogen atom to which they are bonded form a4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally includefrom 1 to 4 of the same or different additional heteroatoms selectedfrom the group consisting of O, N and S.

In one embodiment, the chromone derivative has structural formula (VII):

wherein,

m is 1, 2, 3, or 4;

n is 0, 1, 2, 3, 4, or 5;

each R¹, R², and R³ are independently —R^(a), halo, —O—, ═O, —OR^(b),—SR^(b), —S, ═S, —NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CN,—OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O—, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O—, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b), or —NR^(b)C(NR^(b))NR^(c)R^(c); and at least oneof R¹ and R² is —OH;

R^(a) is selected from the group consisting of a sugar ring, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

each R^(b) is independently hydrogen or R^(a); and

each R^(c) is independently R^(b) or alternatively, the two R^(c)s maybe taken together with the nitrogen atom to which they are bonded form a4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally includefrom 1 to 4 of the same or different additional heteroatoms selectedfrom the group consisting of O, N and S.

In one embodiment, the phenol-based antioxidant suitable for the presentinvention includes, but is not limited to, cinnamic acid derivatives;flavones; isoflavones; chromones; coumarins; chalcones; and combinationsthereof.

In another embodiment, the phenol-based antioxidant suitable for thepresent invention includes, but is not limited to, caffeic acid, ferulicacid, sinapic acid, rosmarinic acid, chlorogenic acid, cichoric acid,caftaric acid, echinacoside, myricitrin, myricetin, apigenin,kaempferol, rhoifolin, luteolin, diosmin, apiin, morin, neodiosmin,quercetin, rutin, cupressuflavone, datiscetin, diosmetin, fisetin,galangin, gossypetin, geraldol, hinokiflavone, scutellarein, flavonol,primuletin, pratol, robinetin, quercetagetin, sinensetin, chrysoeriol,isorhamnetin, vitexin, isoquercitrin, daidzin, daidzein, biochamin A,prunetin, genistin, glycitein, glycitin, genistein,6,7,4′-trihydroxyisoflavone, 7,3′,4′-trihydroxyisoflavone, chromone,visnagin, sophorachromone A, volkensiachromone, sawarachromone,mycochromone, 2-carboxyethenyl-5,7-dihydroxychromone,7-hydroxy-5-(4-hydroxy-2-oxopentyl)-2-methylchromone-7-O-beta-D-glucopyranoside,8-glucosyl-5,7-dihydroxy-2-(1-methylpropyl)chromone, diacromone,hymecromone, 5-hydroxy-2-methylchromone, cassiachromone, coumarin,coumestrol, dalbergin, daphnetin, esculetin, citropten, umbelliferone,scopoletin, xanthotoxol, psoralen, bergapten, fraxetin, butein,phloridzin, echinatin, marein, isoliquiritigenin, phloretin,polyhydroxychalcones, pholoretin, trilobatin, naringin dihydrochalcone,neohesperidin dihydrochalcone, naringenin, homoeriodictyol, hesperetin,myricitrin, enzymatically modified isoquercitrin (EMIQ), and acombination thereof.

Compositions

The present sweet enhancer(s) and photostabilizer(s) can be formulatedtogether in a liquid composition, which may be a ingestible compositionor a non-ingestible composition. The sweet enhancer may be in a sweetflavor enhancing amount, while the photostabilizer may be in a sweetenhancer stabilizing amount. In the liquid composition, the sweetenhancer(s) and photostabilizer(s) may be completely dissolved orpartially dissolved in the liquid.

In one embodiment of the present invention, the liquid compositioncomprises a sweet enhancer and a phenol-based antioxidant, wherein thesweet enhancer has a structural formula (II), or a tautomer, salt, orsolvate thereof; and the phenol-based antioxidant is selected from thegroup consisting of a flavanone derivative having a structural formula(VII), a phenylpropenioc carbonyl compound having a structural formula(V), a coumarine derivative having structural formula (IV), and acombination thereof. In certain more specific embodiments of the liquidcomposition, the structural formula (II) includes any subgenus andspecies of formula (II) as described herein. In certain more specificembodiments of the liquid composition, the phenol-based antioxidant isselected from the group consisting of EMIQ, chlorogenic acid, caffeicacid, ferulic acid, sinapinic acid, scopoletin, daphnetin, and acombination thereof.

In one embodiment of the present invention, the liquid compositioncomprises a sweet enhancer and a phenol-based antioxidant, wherein thesweet enhancer has a structural formula (I), or a tautomer, salt, orsolvate thereof; and the phenol-based antioxidant is selected from thegroup consisting of a chromone derivative having a structural formula(III), a flavanone derivative having a structural formula (VII), acoumarine derivative having structural formula (IV), and a combinationthereof. In certain more specific embodiments of the liquid composition,the structural formula (I) includes any subgenus and species of formula(I) as described herein. In certain more specific embodiments of theliquid composition, the phenol-based antioxidant is selected from thegroup consisting of EMIQ, rutin, daphnetin, and a combination thereof.

In one embodiment of the present invention, the liquid compositioncomprises a sweet enhancer and a phenol-based antioxidant, wherein thesweet enhancer has a structural formula (Ie), or a tautomer, salt, orsolvate thereof; and the phenol-based antioxidant is selected from thegroup consisting of a chromone derivative having a structural formula(III), a phenylpropenioc carbonyl compound having a structural formula(V), and a combination thereof. In certain more specific embodiments ofthe liquid composition, the structural formula (Ie) includes anysubgenus and species of formula (Ie) as described herein. In certainmore specific embodiments of the liquid composition, the phenol-basedantioxidant is chlorogenic acid (CGA) or EMIQ.

The ingestible composition includes both “food or beverage products” and“non-edible products”. The non-ingestible composition includes flavorconcentrates in form of semi-solid or liquid. By “Food or beverageproducts”, it is meant any edible product intended for consumption byhumans or animals, including semi-solids or liquids (e.g., beverages).The term “non-edible products” or “noncomestible composition” includessupplements, nutraceuticals, functional food products (e.g., any freshor processed food claimed to have a health-promoting and/ordisease-preventing properties beyond the basic nutritional function ofsupplying nutrients), pharmaceutical and over the counter medications,oral care products such as dentifrices and mouthwashes, cosmeticproducts, and other personal care products that use sucrose and or othersweeteners.

In one embodiment, the compounds of the present invention can be used atvery low concentrations on the order of a few parts per million, incombination with one or more known sweeteners, natural or artificial, soas to reduce the concentration of the known sweetener required toprepare an ingestible composition having the desired degree ofsweetness.

Commonly used known or artificial sweeteners for use in suchcombinations of sweeteners include but are not limited to the commonsaccharide sweeteners, e.g., sucrose, fructose, glucose, and sweetenercompositions comprising natural sugars, such as corn syrup (includinghigh fructose corm syrup) or other syrups or sweetener concentratesderived from natural fruit and vegetable sources, semi-synthetic “sugaralcohol” sweeteners such as erythritol, isomalt, lactitol, mannitol,sorbitol, xylitol, maltodextrin, and the like, and artificial sweetenerssuch as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, andalitame. Sweeteners also include cyclamic acid, mogroside, tagatose,maltose, galactose, mannose, sucrose, fructose, lactose, neotame andother aspartame derivatives, glucose, D-tryptophan, glycine, maltitol,lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), stevioside, rebaudioside A and other sweetStevia-based glycosides, carrelame and other guanidine-based sweeteners,etc. The term “sweeteners” also includes combinations of sweeteners asdisclosed herein.

The present compounds can also be provided, individually or incombination, with any ingestible composition known or later discovered.For example, the ingestible composition can be a comestible compositionor noncomestible composition. By “comestible composition”, it is meantany composition that can be consumed as food by humans or animals,including gel, paste, foamy material, semi-solids, liquids, or mixturesthereof. By “noncomestible composition”, it is meant any compositionthat is intended to be consumed or used by humans or animals not asfood, including solids, gel, paste, foamy material, semi-solids,liquids, or mixtures thereof. The noncomestible composition includes,but is not limited to medical composition, which refers to anoncomestible composition intended to be used by humans or animals fortherapeutic purposes. By “animal”, it includes any non-human animal,such as, for example, farm animals and pets.

The liquid composition of the present invention can be either in form ofa ready-to-be-consumed final product, such as the categories discussedherein below, or in form of a intermediate and/or precursor which willbe further processed to become a ready-to-be-consumed final product.

Examples of food and beverage products or formulations include, but arenot limited to sweet coatings, frostings, or glazes for comestibleproducts or any entity included in the Soup category, the DriedProcessed Food category, the Beverage category, the Ready Meal category,the Canned or Preserved Food category, the Frozen Processed Foodcategory, the Chilled Processed Food category, the Snack Food category,the Baked Goods category, the Confectionary category, the Dairy Productcategory, the Ice Cream category, the Meal Replacement category, thePasta and Noodle category, and the Sauces, Dressings, Condimentscategory, the Baby Food category, and/or the Spreads category.

In general, the Soup category refers to canned/preserved, dehydrated,instant, chilled, UHT and frozen soup. For the purpose of thisdefinition soup(s) means a food prepared from meat, poultry, fish,vegetables, grains, fruit and other ingredients, cooked in a liquidwhich may include visible pieces of some or all of these ingredients. Itmay be clear (as a broth) or thick (as a chowder), smooth, pureed orchunky, ready-to-serve, semi-condensed or condensed and may be servedhot or cold, as a first course or as the main course of a meal or as abetween meal snack (sipped like a beverage). Soup may be used as aningredient for preparing other meal components and may range from broths(consomme) to sauces (cream or cheese-based soups).

In general, the Soup category refers to canned/preserved, dehydrated,instant, chilled, UHT and frozen soup. For the purpose of thisdefinition soup(s) means a food prepared from meat, poultry, fish,vegetables, grains, fruit and other ingredients, cooked in a liquidwhich may include visible pieces of some or all of these ingredients. Itmay be clear (as a broth) or thick (as a chowder), smooth, pureed orchunky, ready-to-serve, semi-condensed or condensed and may be servedhot or cold, as a first course or as the main course of a meal or as abetween meal snack (sipped like a beverage). Soup may be used as aningredient for preparing other meal components and may range from broths(consomme) to sauces (cream or cheese-based soups).

“Dehydrated and Culinary Food Category” usually means: (i) Cooking aidproducts such as: powders, granules, pastes, concentrated liquidproducts, including concentrated bouillon, bouillon and bouillon likeproducts in pressed cubes, tablets or powder or granulated form, whichare sold separately as a finished product or as an ingredient within aproduct, sauces and recipe mixes (regardless of technology); (ii) Mealsolutions products such as: dehydrated and freeze dried soups, includingdehydrated soup mixes, dehydrated instant soups, dehydratedready-to-cook soups, dehydrated or ambient preparations of ready-madedishes, meals and single serve entrees including pasta, potato and ricedishes; and (iii) Meal embellishment products such as: condiments,marinades, salad dressings, salad toppings, dips, breading, battermixes, shelf stable spreads, barbecue sauces, liquid recipe mixes,concentrates, sauces or sauce mixes, including recipe mixes for salad,sold as a finished product or as an ingredient within a product, whetherdehydrated, liquid or frozen.

The Beverage category usually means beverages, beverage mixes andconcentrates, including but not limited to, carbonated andnon-carbonated beverages, alcoholic and non-alcoholic beverages, readyto drink beverages, liquid concentrate formulations for preparingbeverages such as sodas, and dry powdered beverage precursor mixes. TheBeverage category also includes the alcoholic drinks, the soft drinks,sports drinks, isotonic beverages, and hot drinks. The alcoholic drinksinclude, but are not limited to beer, cider/perry, FABs, wine, andspirits. The soft drinks include, but are not limited to carbonates,sucha as colas and non-cola carbonates; fruit juice, such as juice,nectars, juice drinks and fruit flavoured drinks; bottled water, whichincludes sparkling water, spring water and purified/table water;functional drinks, which can be carbonated or still and include sport,energy or elixir drinks; concentrates, such as liquid and powderconcentrates in ready to drink measure. The hot drinks include, but arenot limited to coffee, such as fresh, instant, and combined coffee; tea,such as black, green, white, oolong, and flavored tea; and other hotdrinks including flavour-, malt- or plant-based powders, granules,blocks or tablets mixed with milk or water.

The Snack Food category generally refers to any food that can be a lightinformal meal including, but not limited to Sweet and savoury snacks andsnack bars. Examples of snacke food include, but are not limited tofruit snacks, chips/crisps, extruded snacks, tortilla/corn chips,popcorn, pretzels, nuts and other sweet and savoury snacks. Examples ofsnack bars include, but are not limited to granola/muesli bars,breakfast bars, energy bars, fruit bars and other snack bars.

The Baked Goods category generally refers to any edible product theprocess of preparing which involves exposure to heat or excessivesunlight. Examples of baked goods include, but are not limited to bread,buns, cookies, muffins, cereal, toaster pastries, pastries, waffles,tortillas, biscuits, pies, bagels, tarts, quiches, cake, any bakedfoods, and any combination thereof.

The Ice Cream category generally refers to frozen dessert containingcream and sugar and flavoring. Examples of ice cream include, but arenot limited to: impulse ice cream; take-home ice cream; frozen yoghurtand artisanal ice cream; soy, oat, bean (e.g., red bean and mung bean),and rice-based ice creams.

The Confectionary category generally refers to edible product that issweet to the taste. Examples of confectionary include, but are notlimited to candies, gelatins, chocolate confectionery, sugarconfectionery, gum, and the likes and any combination products.

The Meal Replacement category generally refers to any food intended toreplace the normal meals, particularly for people having health orfitness concerns. Examples of meal replacement include, but are notlimited to slimming products and convalescence products.

The Ready Meal category generally refers to any food that can be servedas meal without extensive preparation or processing. The ready mealincludes products that have had recipe “skills” added to them by themanufacturer, resulting in a high degree of readiness, completion andconvenience. Examples of ready meal include, but are not limited tocanned/preserved, frozen, dried, chilled ready meals; dinner mixes;frozen pizza; chilled pizza; and prepared salads.

The Pasta and Noodle category includes any pastas and/or noodlesincluding, but not limited to canned, dried and chilled/fresh pasta; andplain, instant, chilled, frozen and snack noodles.

The Canned/Preserved Food category includes, but is not limited tocanned/preserved meat and meat products, fish/seafood, vegetables,tomatoes, beans, fruit, ready meals, soup, pasta, and othercanned/preserved foods.

The Frozen Processed Food category includes, but is not limited tofrozen processed red meat, processed poultry, processed fish/seafood,processed vegetables, meat substitutes, processed potatoes, bakeryproducts, desserts, ready meals, pizza, soup, noodles, and other frozenfood.

The Dried Processed Food category includes, but is not limited to rice,dessert mixes, dried ready meals, dehydrated soup, instant soup, driedpasta, plain noodles, and instant noodles.

The Chill Processed Food categroy includes, but is not limited tochilled processed meats, processed fish/seafood products, lunch kits,fresh cut fruits, ready meals, pizza, prepared salads, soup, fresh pastaand noodles.

The Sauces, Dressings and Condiments category includes, but is notlimited to tomato pastes and purees, bouillon/stock cubes, herbs andspices, monosodium glutamate (MSG), table sauces, soy based sauces,pasta sauces, wet/cooking sauces, dry sauces/powder mixes, ketchup,mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickledproducts, and other sauces, dressings and condiments.

The Baby Food category includes, but is note limited to milk- orsoybean-based formula; and prepared, dried and other baby food.

The Spreads category includes, but is not limited to jams and preserves,honey, chocolate spreads, nut based spreads, and yeast based spreads.

The Dairy Product category generally refers to edible product producedfrom mammal's milk. Examples of dairy product include, but are notlimited to drinking milk products, cheese, yoghurt and sour milk drinks,and other dairy products.

Typically at least a sweet flavor enhancing amount of one or more of thepresent compound will be added to the liquid composition, optionally inthe presence of known sweeteners, e.g., so that the sweet flavormodified ingestible composition has an increased sweet taste as comparedto the ingestible composition prepared without the compounds of thepresent invention, as judged by human beings or animals in general, orin the case of formulations testing, as judged by a majority of a panelof at least eight human taste testers, via procedures commonly known inthe field.

The concentration of sweet flavoring agent needed to modulate or improvethe flavor of the ingestible composition will of course depend on manyvariables, including the specific type of the ingestible composition andits various other ingredients, especially the presence of other knownsweet flavoring agents and the concentrations thereof, the naturalgenetic variability and individual preferences and health conditions ofvarious human beings tasting the compositions, and the subjective effectof the particular compound on the taste of such chemosensory compounds.

One application of the present compounds is for modulating (inducing,enhancing or inhibiting) the sweet taste or other taste properties ofother natural or synthetic sweet tastants, and comestible compositionsmade therefrom. A broad but also low range of concentrations of thecompounds or entities of the present invention would typically berequired, i.e., from about 0.001 ppm to 100 ppm, or narrower alternativeranges from about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about30 ppm, from about 0.05 ppm to about 10 ppm, from about 0.01 ppm toabout 5 ppm, or from about 0.02 ppm to about 2 ppm, or from about 0.01ppm to about 1 ppm.

Photostability of the sweet enhancer can be measured via photostabilitytest which is typically done under controlled conditions, often in asealed chamber where exact exposure levels to the spectra of light aproduct is likely to encounter, can be delivered for precise analysis ofthe effects. The light levels used in photostability testing aregenerally high enough to accelerate hours, days, weeks, months, or evenyears worth of light exposure down to seconds, minutes, or hours in thetesting chamber. Monitoring of the exposure levels is critical and iseither done by built-in measurement equipment within the chamber or byexternal instrumentation. This type of exact, accelerated,laboratory-level photostability testing is typical for thepharmaceutical, paint, ink, and dye manufacturing industries amongothers. Visible light and UVA are the prime spectra of concern due tothe abundance of both types in sunlight and typical indoor lightingwhich are the most likely light sources to be encountered by thesephoto-sensitive products when in use or in-situ.

Preparations

The starting materials used in preparing the compounds of the invention,i.e. the various structural subclasses and species of the compounds ofthe synthetic precursors of the present compounds of Formula (I), areoften known compounds, or can be synthesized by known methods describedin the literature, or are commercially available from various sourceswell known to those of ordinary skill in the art, such as for example,Sigma-Aldrich Corporation of St. Louis, Mo. USA and their subsidiariesFluka and Riedel-de Haen, at their various other worldwide offices, andother well known chemical suppliers such as Fisher Scientific, TCIAmerica of Philadelphia, Pa., ChemDiv of San Diego, Calif., Chembridgeof San Diego, Calif., Asinex of Moscow, Russia, SPECS/BIOSPECS of theNetherlands, Maybridge of Cornwall, England, Acros, TimTec of Russia,Comgenex of South San Francisco, Calif., and ASDI Biosciences of Newark,Del.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out the synthesis of many starting materialsand subsequent manipulations without further direction, that is, it iswell within the scope and practice of the skilled artisan to carry outmany desired manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification, saponification, nitrations,hydrogenations, reductive animation and the like. These manipulationsare discussed in standard texts such as March's Advanced OrganicChemistry (3d Edition, 1985, Wiley-Interscience, New York), Feiser andFeiser's Reagents for Organic Synthesis, and in the various volumes andeditions oiMethoden der Organischen Chemie (Houben-Weyl), and the like.Many general methods for preparation of starting materials comprisingvariously substituted heterocyclic, hetereoaryl, and aryl rings (theprecursors of Ar, hAr¹, and/or hAr²) can be found in Methoden derOrganischen Chemie (Houben-Weyl), whose various volumes and editions areavailable from Georg Thieme Verlag, Stuttgart. The entire disclosures ofthe treatises recited above are hereby incorporated by reference intheir entirieties for their teachings regarding methods for synthesizingorganic compounds and their precursors.

The skilled artisan will also readily appreciate that certain reactionsare best carried out when other functionality is masked or protected inthe molecule, thus avoiding any undesirable side reactions and/orincreasing the yield of the reaction. Often the skilled artisan utilizesprotecting groups to accomplish such increased yields or to avoid theundesired reactions. These reactions are found in the literature and arealso well within the scope of the skilled artisan. Examples of many ofthese manipulations can be found for example in T. Greene and P. Wuts,Protecting Groups in Organic Synthesis, 3^(r) Ed., John Wiley & Sons(1999).

Some exemplary synthetic methods for preparing the present compounds areillustrated in the Schemes 1 to 6 below.

As shown in Scheme 1, substituted 4-aminoquinoline-3-carboxylatederivatives (VI) can be prepared by reacting the corresponding anilinesI with 2-(alkoxymethylene)malonates II followed by cyclization of theintermediates III under elevated temperature to provide the hydroxylintermediates IV that can be treated with POCl₃ or SO₂Cl₂ to provide thecorresponding chloride derivatives V that can be further treated withammonia or amines to give the desired amino-quinolines VI. (Kamal, A. etal. Bioorg. Med. Chem. 2005, 13, 2021-2029; Fryer, R. I. et al. J. Med.Chem. 1993, 36, 1669-1673; Bi, Y. et al. Bioorg. Med. Chem. Lett. 2004,14, 1577-1580; Li, S. Y. et al. Bioorg. Med. Chem. 2006, 14, 7370-7376.Koga, H. et al. J. Med. Chem. 1980, 23, 1358-1363.).

Substituted 4-aminoquinoline-3-carboxylate derivatives (VI) can also beprepared by reacting the corresponding 2-aminobenzoic acids VIII withphosgene or equivalent to provide the isatoic anhydrides IX that can befurther reacted with X to give the derivatives IV (Mai, A. et al. J.Med. Chem. 2006, 49, 6897-6907. Beutner, G. L. et al. J. Org. Chem.2007, 72, 7058-7061, and references cited therein), which can beconverted to VI as described in Scheme 1.

Alternatively, substituted 4-aminoquinoline-3-carboxylate derivatives(VI) can be prepared by reacting the corresponding amino benzonitrilesXI with X to provide the amino derivatives XII (Sestili, I. et al. Eur.J. Med. Chem. 2004, 39, 1047-1057. Doucet-Personeni, C. et al. J. Med.Chem. 2001, 44, 3203-3215. Veronese, A. C. et al. Tetrahedron 1995, 51,12277-12284, and the references cited therein) that can be furtheralkylated to give the substituted aminoquinolines VI as shown in Scheme3. Amino quinolines XII can also be prepared via a Michael addition ofthe 2-amino benzonitriles XI to various α,β-unsaturated carboxylatederivatives XIII, XIV or XV to provide the adducts XVI (MacNab, H. etal. Synthesis 2009, 2171-2174. Vicario, J. L. Synthesis 2007, 2065-2092,and references cited therein.) that can be further cyclized to give theamino quinolines XII (Han, G. F. et al. Synth. Commun. 2009, 39,2492-2505. Tabarrini, O. et al. Bioorg. Med. Chem. 2001, 9, 2921-2928.Shutske, G. M. et al. J. Med. Chem. 1989, 32, 1805-1813, and referencescited therein.).

As described in Scheme 4, hydrolysis of 4-aminoquinoline-3-carboxylatederivatives VI or XII in the presence of NaOH provide4-aminoquinoline-3-carboxylic acids XVII (Zhao, Y. L. et al. Eur. J.Med. Chem. 2005, 40, 792-797) which can be further coupled with aminesXXII under standard conditions to give 4-aminoquinoline-3-carboxamidederivatives XVIII. When R³ and/or R⁴=H, 4-aminoquinoline-3-carboxylatesVI or XII can be further functionalized by coupling with acids XXIII togive 4-carboxamidoquinoline-3-carboxylates XIX. Compound XIX can befurther hydrolyzed to the acids XX that can be further coupled to theamines XXII to provide amide derivatives XXI.

Compound [1,2,6]thiadiazine-2,2-dioxides and fused[1,2,6]thiadiazine-2,2-dioxide derivatives such as, for example,1H-benzo[c][1,2,6]thiadiazine-2,2-dioxides can be synthesized from2-amino nitriles, 2-amino ketones, or 2-amino carboxyl derivatives A orC (Scheme 5), by reaction with NH₂SO₂C₁ (Hirayama et al., Bioorg. & Med.Chem. 2002, 10, 1509; Kanbe et al., Bioorg. & Med. Chem. Lett. 2006, 16,4090 and references cited therein) or NH₂SO₂NH₂ (Maryanoff et al., J.Med. Chem. 2006, 49, 3496, and references cited therein) and followed bycyclization in the presence of NaOH (Goya et al., Heterocycles, 1986,24, 3451; Albrecht et al., J. Org. Chem. 1979, 44, 4191; Goya et al.,Arch. Pharm. (Weinheim) 1984, 317, 777). The condensation of thecorresponding 1,3-dicarbonyl derivatives, α,β-unsaturated carbonylderivatives with sulfamide derivatives (Scheme 4) also results in theformation of [1,2,6]thiadiazine-2,2-dioxide derivatives (Wright, J. Org.Chem. 1964, 29, 1905).

Compound 1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide derivatives F aresynthesized from the same starting materials D (Scheme 6) via theirreactions with sulfamide or sulfamoyl chloride, followed by cyclizationwith NaOH. Direct reaction of compounds D with sulfamide in the presenceof DBU at the elevated temperature also resulted in the formation of1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide derivatives F (Maryanoff etal., J. Med. Chem. 2006, 49, 3496, and references cited therein).

EXAMPLES

Having now generally described the invention, the same will be morereadily understood by reference to the following examples, which areprovided by way of illustration and are not intended as limiting. It isunderstood that various modifications and changes can be made to theherein disclosed exemplary embodiments without departing from the spiritand scope of the invention.

Example 1: 4-amino-6-methoxyquinoline-3-carboxylic Acid

To a stirred solution of ethyl 4-amino-6-methoxyquinoline-3-carboxylate(Example 1a, 1.23 g, 5.0 mmol) in EtOH (20.0 mL) was added aqueous NaOH(2.0 N, 5.0 mL) at room temperature. The reaction mixture was thenrefluxed for 3 hr. The solution was then filtered and washed with water.The filtrate was cooled to 0° C. and neutralized carefully with 1 N HClto pH 7. Most of the EtOH was removed under reduced pressure, and theprecipitate was collected by filtration, washed with cold water, anddried under vacuum to give the title compound as an off-white solid(1.01 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (s, 3H), 7.40 (dd,J=2.8, 9.4 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 8.77(s, 1H). MS 219 (MH⁺).

Example 1a: ethyl 4-amino-6-methoxyquinoline-3-carboxylate

A mixture of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Example1b, 796 mg, 3.0 mmol) and ammonia (25% aqueous solution, 10 mL) inisopropanol (40 mL) was stirred at 110° C. in a pressure reactorovernight. Most of the solvent was then removed under reduced pressure,and the reaction mixture was diluted with water. The precipitate wascollected by filtration, washed with cold water, and dried under vacuumto give the title compound as an off-white solid (680 mg, 92%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.33 (t, J=7.0 Hz, 3H), 3.88 (s, 3H), 4.32 (q,J=7.0 Hz, 2H), 7.36 (dd, J=2.8, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H),7.74 (d, J=2.8 Hz, 1H), 8.23 (bs, 2H), 8.77 (s, 1H). MS 247 (MH⁺).

Example 1b: ethyl 4-chloro-6-methoxyquinoline-3-carboxylate

A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Exampleic, 1.24 g, 5.0 mmol) in POCl₃ was refluxed under nitrogen for 3 hrs.The solution was cooled to room temperature and evaporated under reducedpressure. The residue was carefully quenched with ice, and neutralizedwith 2.0 N NaOH to pH 7. The precipitate was collected by filtration,washed with cold water, and dried under vacuum to give the titlecompound as a pale-yellow solid (1.29 g, 97%). ¹H NMR (400 MHz, DMSO-d₆)δ 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d,J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),8.97 (s, 1H). MS 266, 268 (MH⁺).

Example 1c: ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate

A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120° C.under nitrogen for 4 hrs. The solution was cooled to room temperatureand Ph₂O (100 mL) was added. The reaction mixture was refluxed at 260°C. under nitrogen for 8 hrs. The solution was cooled to room temperatureand diluted with hexanes.

The resultant precipitate was collected by filtration, washed with 25%ethyl acetate in hexanes, and dried under vacuum to give ethyl4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale-yellow solid (4.21g, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (t, J=7.0 Hz, 3H), 3.83 (s,3H), 4.19 (q, J=7.0 Hz, 2H), 7.32 (dd, J=3.2, 9.6 Hz, 1H), 7.55 (d,J=3.2 Hz, 1H), 7.56 (d, J=9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS248 (MH⁺).

Example 2:4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)-propoxy)-2-methylquinoline-3-carboxylate(Example 2a) as an off-white solid (41%). ¹H NMR (400 MHz, DMSO-d₆) δ0.73 (t, J=7.6 Hz, 3H), 1.25 (s, 6H), 1.33-1.42 (m, 2H), 2.76 (s, 3H),3.00-3.05 (m, 2H), 4.16 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.89 (t, J=5.8 Hz, 1H), 8.85 (bs, 1H),12.28 (bs, 1H), 12.78 (bs, 1H). MS 360 (MH⁺).

Example 2a: ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-methylquinoline-3-carboxylate

To a solution of3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221, 1.38 g, 5.0 mmol) andethyl acetoacetate (0.66 g, 5.0 mmol) in dry toluene (150 mL) was addedSnCl₄ (2.61 g, 10.0 mmol) dropwise via syringe at room temperature undernitrogen. After 1 hr at room temperature, the reaction mixture wasrefluxed for an additional 5 hrs. The solution was cooled to roomtemperature and the solvent removed under reduced pressure. The residuewas diluted with EtOAc, and aqueous NaOH (2N) was added at roomtemperature to pH >8. The solution was filtered and the organic layerseparated. The aqueous layer was extracted with EtOAc (5×). The combinedorganic layers was washed with brine, and dried over Na₂SO₄. Afterevaporation of the solvent, the residue was purified by chromatographyon silica gel (0.5% MeOH in EtOAc) to give the title compound as anoff-white solid (1.63 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.73 (t,J=7.6 Hz, 3H), 1.25 (s, 6H), 1.32 (t, J=7.4 Hz, 3H), 1.35-1.42 (m, 2H),2.54 (s, 3H), 3.00-3.05 (m, 2H), 4.12 (s, 2H), 4.31 (q, J=7.4 Hz, 2H),6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H),7.80 (t, J=5.6 Hz, 1H), 8.08 (s, 2H). MS 388 (MH⁺).

Example 3: 4-amino-6-methoxy-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-6-methoxy-2-methylquinoline-3-carboxylate (Example 3a) as awhite solid (87%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.83 (s, 3H), 3.90 (s,3H), 7.57 (dd, J=2.4, 8.2 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.10 (d,J=2.4 Hz, 1H), 9.39 (s, 1H), 9.67 (s, 1H). MS 233 (MH⁺).

Example 3a: ethyl 4-amino-6-methoxy-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-5-methoxybenzonitrile (Campbell,J. B. et al. Synth. Commun. 1989, 19, 2255-2263) and ethyl acetoacetateas an off-white solid (92%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.33 (t, J=6.8Hz, 3H), 2.57 (s, 3H), 3.86 (s, 3H), 4.33 (q, J=6.8 Hz, 2H), 7.28 (dd,J=2.8, 9.2 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.60 (bs, 2H), 7.63 (d,J=2.8 Hz, 1H). MS 261 (MH⁺).

Example 4: 4-amino-2-phenylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-2-phenylquinoline-3-carboxylate (Example 4a) as an off-whitesolid (33%). ¹H NMR (400 MHz, DMSO-d6) δ 7.39-7.52 (m, 7H), 7.79 (m,3H), 8.33 (d, J=8.0 Hz, 1H), 12.63 (bs, 1H). MS 265 (MH⁺).

Example 4a: ethyl 4-amino-2-phenylquinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and ethyl3-oxo-3-phenylpropanoate as a yellow solid (45%). ¹H NMR (400 MHz,DMSO-d₆) δ 0.72 (t, J=8.0 Hz, 3H), 3.92 (q, J=8.0 Hz, 2H), 7.44 (m, 5H),7.50 (m, 1H), 7.61 (bs, 2H), 7.73 (m, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.37(d, J=8.0 Hz, 1H). MS 293 (MH⁺).

Example 5: 4-amino-2-ethylquinoline-3-carboxylic Acid

Prepared as in Example 2 from methyl4-amino-2-ethylquinoline-3-carboxylate (Example 5a) as a white solid(26%). ¹H NMR (400 MHz, DMSO-d₆+1 drop D₂O) δ 1.24 (t, J=8.0 Hz, 3H),3.28 (q, J=8.0 Hz, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),7.83 (t, J=8.0 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H)). MS 217 (MH⁺).

Example 5a: ethyl 4-amino-2-phenylquinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and methyl3-oxopentanoate as a solid (27%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.18 (t,J=8.0 Hz, 3H), 2.88 (q, J=8.0 Hz, 2H), 3.86 (s, 3H), 7.40 (m, 1H), 7.44(bs, 2H), 7.64 (m, 1H), 7.68 (m, 1H), 8.26 (d, J=8.0 Hz, 1H). MS 231(MH⁺).

Example 6: 4-amino-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-2-methylquinoline-3-carboxylate (Example 6a) as a off-whitesolid (41%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.05 (t, J=8.0 Hz, 3H), 2.84(s, 3H), 7.56 (bs, 1H), 7.76 (m, 1H), 7.82 (bs, 1H), 8.39 (d, J=8.0 Hz,1H), 8.99 (bs, 1H), 12.00 (bs, 1H), 12.98 (bs, 1H). MS 203 (MH⁺).

Example 6a: ethyl 4-amino-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and ethyl3-oxobutanoate as a yellow solid (32%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.33(t, J=8.0 Hz, 3H), 2.61 (s, 3H), 4.34 (q, J=8.0 Hz, 2H), 7.41 (m, 1H),7.66 (m, 2H), 7.74 (bs, 2H), 8.27 (d, J=8.0 Hz, 1H). MS 231 (MH⁺).

Example 7:4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-ethyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from methyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-ethylquinoline-3-carboxylate(Example 7a) as a solid (75%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.75 (t,J=8.0 Hz, 3H), 1.03 (t, J=8.0 Hz, 3H), 1.27 (s, 6H), 1.39 (m, 2H), 3.04(q, J=4.0 Hz, 2H), 3.45 (q, J=4.0 Hz, 2H), 4.17 (s, 2H), 7.04 (d, J=8.0Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.90 (t, J=4.0Hz, 1H), 8.89 (bs, 1H), 12.75 (bs, 1H). MS 374 (MH⁺).

Example 7a: methyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-ethylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221) and methyl 3-oxopentanoateas a yellow solid (17%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.75 (t, J=8.0 Hz,3H), 1.17 (t, J=8.0 Hz, 3H), 1.26 (s, 6H), 1.40 (m, 2H), 2.84 (q, J=8.0Hz, 2H), 3.04 (q, J=8.0 Hz, 2H), 3.85 (s, 3H), 4.13 (s, 2H), 6.88 (d,J=8.0 Hz, 1H), 7.27 (dd, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.81 (m,3H). MS 388 (MH⁺).

Example 8: 4-amino-6-phenoxyquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-6-phenoxyquinoline-3-carboxylate (Example 8a) as a off-whitesolid (50%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (d, J=8.0 Hz, 2H), 7.16(t, J=8.0 Hz, 1H), 7.42 (m, 2H), 7.49 (dd, J=8.0 Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 8.86 (s, 1H). MS 281 (MH⁺).

Example 8a: ethyl 4-amino-6-phenoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-phenoxyquinoline-3-carboxylate (Example 8b) and ammonia as aoff-white solid (82%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.35 (t, J=8.0 Hz,3H), 4.35 (q, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz,1H), 7.40 (m, d, 2H), 7.46 (dd, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H),8.13 (d, J=4.0 Hz, 1H), 8.27 (bs, 2H), 8.87 (s, 1H). MS 309 (MH⁺).

Example 8b: ethyl 4-chloro-6-phenoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl4-hydroxy-6-phenoxyquinoline-3-carboxylate (Example 8c) and POCl₃ as atan solid (96%). ¹H NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=8.0 Hz, 3H),4.40 (q, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 1H),7.50 (t, J=8.0 Hz, 2H), 7.63 (d, J=4.0 Hz, 1H), 7.76 (dd, J=8.0 Hz, 1H),8.21 (d, J=8.0 Hz, 1H), 9.06 (s, 1H). MS 328, 330 (MH⁺).

Example 8c: ethyl 4-hydroxy-6-phenoxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-phenoxyaniline and diethyl2-(ethoxymethylene)malonate as a white solid (41%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.24 (t, J=8.0 Hz, 3H), 4.18 (q, J=8.0 Hz, 2H), 7.07 (d,J=8.0 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.47 (m,2H), 7.69 (d, J=12.0 Hz, 1H), 12.39 (bs, 1H). MS 310 (MH⁺).

Example 9: 4-amino-7-fluoroquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-7-fluoroquinoline-3-carboxylate (Example 9a) as an off whitesolid (66%). ¹H NMR (CD₃OD, 400 MHz) δ 07.49 (m, 2H), 8.50 (dd, J=10.0,5.2 Hz, 1H), 8.94 (s, 1H). MS 207 (MH⁺).

Example 9a: ethyl 4-amino-7-fluoroquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-7-fluoroquinoline-3-carboxylate (Example 9b) and ammonia as anoff white solid (99%). MS 235 (MH⁺).

Example 9b: ethyl 4-chloro-7-fluoroquinoline-3-carboxylate

Prepared as in Example 1b from ethyl7-fluoro-4-hydroxyquinoline-3-carboxylate (Example 9c) and POCl₃ as anoff white solid (96%). MS 254, 256 (MH⁺).

Example 9c: ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate

Prepared as in Example Ic from 3-fluoroaniline and diethyl2-(ethoxymethylene)malonate as a brown solid (51%). MS 236 (MH⁺).

Example 10: 4-amino-6-isopropoxyquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-6-isopropoxyquinoline-3-carboxylate (Example 10a) as a an offwhite solid (94%). ¹H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 3H), 1.32 (s,3H), 4.82 (m, 1H), 7.37 (d, J=9.2 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.78(s, 1H), 8.75 (s, 1H). MS 247 (MH⁺).

Example 10a: ethyl 4-amino-6-isopropoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-isopropoxyquinoline-3-carboxylate (Example 10b) and ammoniaas an off white solid (75%). MS 275 (MH⁺).

Example 10b: 4-chloro-6-isopropoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl4-hydroxy-6-isopropoxyquinoline-3-carboxylate (Example 10c) and POCl₃ asa pale yellow solid (93%). MS 294, 296 (MH⁺).

Example 10c: ethyl 4-hydroxy-6-isopropoxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-isopropoxyaniline and diethyl2-(ethoxymethylene)malonate as a yellow solid (20%). MS 276 (MH⁺).

Example 11: 4-amino-6-methoxy-2-methyl-1,5-naphthyridine-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-6-methoxy-2-methyl-1,5-naphthyridine-3-carboxylate (Example 11a)as an off white solid (56%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.68 (s, 3H),4.02 (s, 3H), 7.21 (d, J=8.8 Hz, 1H), 7.99 (d, J=9.2 Hz, 1H). MS 234(MH⁺).

Example 11a: ethyl4-amino-6-methoxy-2-methyl-1,5-naphthyridine-3-carboxylate

Prepared as in Example 2a from 3-amino-6-methoxypicolinonitrile (Example11b) and ethyl 3-oxobutanoate as an off white solid (45%). MS 262 (MH⁺).

Example 11b: 3-amino-6-methoxypicolinonitrile

To a solution of 6-methoxy-3-nitropicolinonitrile (Piersanti, G. et al.Org. Biomolecular Chem. 2007, 5, 2567-2571) (2.0 g, 11.1 mmol) indiglyme (52 mL) was added dropwise a solution of SnCl₂ (6.35 g, 33.5mmol) in concentrated HCl solution (26 mL) at 0° C. The solution wasstirred at 0° C. for 1 hr, then the reaction mixture was neutralizedwith concentrated NaOH solution, and extracted with EtOAc (2×). Thecombined organic layers were washed with brine, and dried over Na₂SO₄.After evaporation of the solvent, the residue was purified bychromatography on silica gel (50% EtOAc in hexanes) to give3-amino-6-methoxypicolinonitrile (966 mg, 58%) as a brown solid. ¹H NMR(400 MHz, CDCl₃) δ 3.81 (s, 3H), 4.10 (bs, 2H), 6.81 (d, J=8.0 Hz, 1H),7.08 (d, J=8.0 Hz, 1H). MS 150 (MH⁺).

Example 12: 4-amino-2,5-dimethylquinoline-3-carboxylic Acid

Ethyl 4-(4-methoxybenzylamino)-2,5-dimethylquinoline-3-carboxylate(Example 12a, 0.563 g, 1.54 mmol) was dissolved in TFA (8 mL) and theresultant solution was stirred at room temperature for 15 minutes, TFAwas then removed under vacuum to give the crude ethyl4-amino-2,5-dimethylquinoline-3-carboxylate product, which was dissolvedin EtOH (4 mL). To this solution was added NaOH (4.0 N, 3.86 mL) and thereaction mixture was stirred at 100° C. for 1 hr. Water (25 mL) wasadded, and the solvent was decanted away from insoluble material thenacidified with AcOH to pH 5.5. The precipitate was collected byfiltration to give the title compound (300 mg, 90%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 2.78 (s, 3H), 2.88 (s, 3H), 7.30 (d, J=7.2 Hz,1H), 7.58 (d, J=8.0 Hz, 1H), 7.65 (m, 1H), 7.8-8.0 (br, 1H), 12.2-12.9(br, 2H). MS 217 (MH⁺).

Example 12a: ethyl4-(4-methoxybenzylamino)-2,5-dimethylquinoline-3-carboxylate

A solution of ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate(Example 12b, 0.518 g, 1.96 mmol) and (4-methoxyphenyl)methanamine (1.15mL, 8.86 mmol) in toluene (10 mL) and DMF (5 mL) were stirred at 115° C.under nitrogen for 12 hrs. The solvent was removed under vacuum, and theresidue was purified by chromatography on silica gel (0% to 50% EtOAc inhexanes) to give the title compound as an oil (563 mg, 79%). ¹H NMR (400MHz, DMSO-d₆) δ 1.24 (t, J=7.6 Hz, 3H), 2.45 (s, 3H), 2.78 (s, 3H), 3.73(s, 3H), 4.2-4.3 (m, 4H), 6.27 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.4 Hz,2H), 7.19 (m, 3H), 7.48 (m, 1H), 7.58 (d, J=8.4 Hz, 1H). MS 365 (MH⁺).

Example 12b: ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate

A solution of 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (Example 12c)(1.36 g, 7.68 mmol), ethyl 3-oxobutanoate (1.46 mL, 11.5 mmol), and NaOH(0.046 g, 1.15 mmol) in anhydrous dioxane (10 mL) were refluxed undernitrogen for 15 hrs. The solvent was then removed under vacuum, and theresidue was re-dissolved in DMF (15 mL). To this solution was addedPOCl₃ (1.41 mL, 15.4 mmol), and the reaction mixture was stirred at roomtemperature for 45 minutes. The reaction was carefully quenched with icewater (150 mL), and extracted with DCM (2×75 mL). The combined organiclayers were washed with brine, and dried over Na₂SO₄. After evaporationof the solvent, the residue was purified by chromatography on silica geleluting with 50% EtOAc in hexanes to give the title compound as red oil(520 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (t, J=7.6 Hz, 3H), 2.58(s, 3H), 2.97 (s, 3H), 4.46 (q, J=7.6 Hz, 2H), 7.51 (d, J=7.2 Hz, 1H),7.71 (m, 1H), 7.87 (d, J=7.6 Hz, 1H). MS 264, 266 (MH⁺⁾

Example 12c: 5-methyl-H-benzo[d][1,3]oxazine-2,4-dione

Trichloromethyl carbonochloridate (2.04 mL, 16.9 mmol) was added to2-amino-6-methylbenzoic acid (2.13 g, 14.1 mmol) in anhydrous dioxane(32 mL) under nitrogen, then refluxed for 30 minutes. Diethyl ether (100mL) was added, and the precipitated solid was collected by filtration togive 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.4 g, 56%) which wasused without further purification.

Example 13: 4-amino-6-ethoxyquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-6-ethoxyquinoline-3-carboxylate (Example 13a) as an off whitesolid (76%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (t, J=7.2 Hz, 3H), 4.18(q, J=7.2 Hz, 2H), 7.50-7.53 (m, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.95 (d,J=2.0 Hz, 1H), 8.86 (s, 1H), 9.26 (bs, 1H), 9.86 (bs, 1H). MS 233 (MH⁺).

Example 13a: ethyl 4-amino-6-ethoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-ethoxyquinoline-3-carboxylate (Example 13b) and ammonia as anoff white solid (77%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.31-1.40 (m, 6H),4.15 (q, J=7.2 Hz, 2H), 4.31 (q, J=6.8 Hz, 2H), 7.34 (q, J=6.4 Hz, 1H),7.69-7.74 (m, 2H), 8.21 (bs, 2H), 8.77 (s, 1H). MS 261 (MH⁺).

Example 13b: ethyl 4-chloro-6-ethoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl6-ethoxy-4-hydroxyquinoline-3-carboxylate (Example 13c) and POCl₃ aspale yellow solid (100%). ¹H NMR (400 MHz, DMSO-d6) δ 1.34-1.42 (m, 6H),4.21 (q, J=7.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 7.52 (d, J=2.8 Hz, 1H),7.56-7.59 (m, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.94 (s, 1H). MS 280, 282(MH⁺).

Example 13c: ethyl 6-ethoxy-4-hydroxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-ethoxyaniline and diethyl2-(ethoxymethylene)malonate as a white solid (26%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.24-1.37 (m, 6H), 4.09 (q, J=6.8 Hz, 2H), 4.19 (q, J=7.2 Hz,2H), 7.29-7.32 (m, 1H), 7.52-7.56 (m, 2H), 8.47 (s, 1H), 12.27 (s, 1H).MS 262 (MH⁺).

Example 14: 4-amino-6-propoxyquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-6-propoxyquinoline-3-carboxylate (Example 14a) as a white solid(56%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.01 (t, J=7.6 Hz, 3H), 1.77-1.82 (m,2H), 4.06 (t, J=6.8 Hz, 2H), 7.43 (d, J=2.0 Hz, 1H), 7.71-7.78 (m, 2H),8.77 (s, 1H). MS 247 (MH⁺).

Example 14a: 4-amino-6-propoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-propoxyquinoline-3-carboxylate (Example 14b) and ammonia as awhite solid. MS 275 (MH⁺).

Example 14b: ethyl 4-chloro-6-propoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl4-hydroxy-6-propoxyquinoline-3-carboxylate (Example 14c) and POCl₃ as apale yellow solid. MS 294, 296 (MH⁺).

Example 14c: ethyl 4-hydroxy-6-propoxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-propoxyaniline and diethyl2-(ethoxymethylene)malonate as a white solid (65%). ¹H NMR (400 MHz,DMSO-d₆) δ 0.98 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.72-1.77 (m,2H), 3.98 (t, J=6.0 Hz, 2H), 4.16-4.21 (m, 2H), 6.97-6.99 (m, 1H),7.53-7.56 (m, 2H), 8.47 (d, J=5.2 Hz, 1H), 12.27 (s, 1H). MS 276 (MH⁺).

Example 15: 4-amino-5-methoxy-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-5-methoxy-2-methylquinoline-3-carboxylate (Example 15a) as aoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.49 (s, 3H), 4.05 (s, 3H),7.19 (d, J=7.6 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H),9.49 (s, 1H), 9.85 (s, 1H). MS 233 (MH⁺).

Example 15a: ethyl 4-amino-5-methoxy-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-methoxybenzonitrile and ethyl3-oxobutanoate as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.32(t, J=7.2 Hz, 3H), 2.55 (s, 3H), 3.96 (s, 3H), 4.30 (q, J=7.2 Hz, 2H),6.88 (d, J=8.4 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H),8.15 (s, 2H). MS 261 (MH⁺).

Example 16: 4-amino-2-methyl-5-(neopentyloxy)quinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(neopentyloxy)quinoline-3-carboxylate (Example 16a)as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.06 (s, 9H), 2.76 (s,3H), 3.93 (s, 2H), 7.05 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.66(t, J=8.0 Hz, 1H). MS 289 (MH⁺).

Example 16a: ethyl4-amino-2-methyl-5-(neopentyloxy)quinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(neopentyloxy)benzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as a white solid (64%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.06(s, 9H), 1.32 (t, J=6.8 Hz, 3H), 2.54 (s, 3H), 3.86 (s, 2H), 4.31 (q,J=6.8 Hz, 2H). 6.88-6.91 (m, 1H), 7.22-7.25 (m, 1H), 7.50 (t, J=8.0 Hz,1H), 8.06 (s, 2H). MS 317 (MH⁺).

Example 17: 4-amino-2-(carboxymethyl)quinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate (Example 17a) asa white solid (26%). ¹H NMR (400 MHz, DMSO-d6) δ 3.76 (s, 2H), 7.36 (t,J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.64 (d, J=12.0 Hz, 1H), 7.87(bs, 2H), 8.17 (d, J=8.0 Hz, 1H). MS 188 (MH⁺—CH₂CO₂H).

Example 17a: ethyl4-amino-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and diethyl3-oxopentanedioate as a pale yellow solid (25%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.19 (t, J=8.0 Hz, 3H), 1.30 (t, J=8.0 Hz, 3H), 4.08 (m, 4H),4.28 (q, J=8.0 Hz, 2H), 7.50 (m, 1H), 7.73 (m, 2H), 8.10 (bs, 2H), 8.53(d, J=8.0 Hz, 1H). MS 303 (MH⁺).

Example 18:4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate (Example18a) as a white solid (86%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.31-1.36 (m,2H), 1.55-1.62 (m, 4H), 1.80-1.95 (m, 2H), 2.46-2.50 (m, 1H), 2.74 (s,3H), 4.11 (d, J=7.6 Hz, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz,1H), 7.64 (t, J=8.0 Hz, 1H). MS 301 (MH⁺).

Example 18a: ethyl4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCTInt. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a paleyellow solid (75%). MS 329 (MH⁺).

Example 19: 4-amino-5-(cyclopentyloxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(cyclopentyloxy)-2-methylquinoline-3-carboxylate (Example 19a)as a off white solid (83%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.56-1.60 (m,2H), 1.67-1.70 (m, 2H), 1.83-1.87 (m, 2H), 1.92-1.96 (m, 2H), 2.67 (s,3H), 5.05-5.07 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),7.57 (t, J=8.4 Hz, 1H). MS 287 (MH⁺).

Example 19a: ethyl4-amino-5-(cyclopentyloxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cyclopentyloxy)benzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as a yellow solid (40%). MS 315 (MH⁺).

Example 20:4-amino-2,3-butylene-6-methylthieno[2,3-b]pyridine-5-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-2,3-butylene-6-methylthieno[2,3-b]pyridine-5-carboxylate(Example 20a) as a solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.78-1.79 (m, 4H),2.53 (s, 3H), 2.71-2.72 (m, 2H), 2.94-2.96 (m, 2H), 6.86 (s, 2H). MS 263(MH⁺).

Example 20a: ethyl4-amino-2,3-butylene-6-methylthieno[2,3-b]pyridine-5-carboxylate

Prepared as in Example 2a from2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoateas a yellow solid. MS 291 (MH⁺).

Example 21: 4-amino-5-(3,3-dimethylbutyl)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3,3-dimethylbutyl)-2-methylquinoline-3-carboxylate (Example21a) as a white solid (88%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.93 (s, 9H),1.40 (t, J=8.8 Hz, 2H), 2.75 (s, 3H), 3.17 (t, J=8.4 Hz, 2H), 7.35 (d,J=7.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 12.78 (s,1H). MS 287 (MH⁺).

Example 21a: ethyl4-amino-5-(3,3-dimethylbutyl)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(3,3-dimethylbutyl)benzonitrile(Example 21b) and ethyl 3-oxobutanoate as a white solid (95%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.93 (s, 9H), 1.32 (t, J=7.2 Hz, 3H), 1.42-1.46 (m,1H), 2.55 (s, 3H), 3.11-3.15 (m, 2H), 4.33 (q, J=7.2 Hz, 2H), 7.12 (s,2H), 7.19-7.21 (m, 1H), 7.46-7.52 (m, 2H). MS 315 (MH⁺).

Example 21b: 2-amino-6-(3,3-dimethylbutyl)benzonitrile

A suspension of 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile (Example21c, 690 mg, 3.48 mmol) and 10% Pd/C (100 mg) in EtOAc/EtOH (1:1, 20 mL)was stirred under an atmosphere of H₂ with a balloon at room temperatureovernight. The Pd/C was removed by filtration, the filtrate wasconcentrated, and purified by chromatography on silica gel eluting with20% EtOAc in hexanes to give the title compound as a light yellow oil(620 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.92 (s, 9H), 1.36-1.40 (m,2H), 2.52-2.56 (m, 2H), 5.88 (s, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.57 (d,J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 203 (MH⁺).

Example 21c: 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile

To a solution of 2-amino-6-bromobenzonitrile (1.97 g, 10.0 mmol),3,3-dimethylbut-1-yne (2.46 g, 30 mmol), K₂CO₃ (2.76 g, 20.0 mmol), andCuI (191 mg, 0.1 mmol) in DME/H₂O (4:1, 50 mL) was added Pd(PPh₃)₄ (1.16g, 0.1 mmol) at room temperature under nitrogen. The reaction mixturewas refluxed under nitrogen overnight. After it was cooled down to roomtemperature, the reaction was quenched with brine, extracted with EtOAc.The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by chromatography on silica geleluting with 20% EtOAc in hexanes to give the title compound as a lightbrown oil (1.84 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (s, 9H), 6.10(s, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.18-7.22 (m,1H). MS 199 (MH⁺).

Example 22: 4-amino-5-(2-ethylbutoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-ethylbutoxy)-2-methylquinoline-3-carboxylate (Example 22a)as a white solid (45%). M.p.: 145-151° C. ¹H NMR (400 MHz, DMSO-d₆) δ0.90 (t, J=8 Hz, 6H), 1.48-1.41, (m, 4H), 1.84-1.78 (m, 1H), 2.73 (s,3H), 4.11 (d, J=8 Hz, 2H), 6.99 (d, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H),7.59 (t, J=8 Hz, 1H), 8.40 (brs, 1H), 11.09 (brs, 1H), 13.91 (brs, 1H).MS 303 (MH⁺).

Example 22a: ethyl4-amino-5-(2-ethylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(2-ethylbutoxy)benzonitrile(Example 22b) and ethyl 3-oxobutanoate as a white solid (89%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.90 (t, J=8 Hz, 6H), 1.32 (t, J=8 Hz, 3H),1.48-1.41 (m, 4H), 1.79-1.73 (m, 1H), 2.54 (s, 3H), 4.08 (d, J=4 Hz,2H), 4.31 (q, J=8 Hz, 2H), 6.92 (dd, J=2, 8 Hz, 1H), 7.23 (dd, J=2, 8Hz, 1H), 7.50 (t, J=8 Hz, 1H), 8.04 (brs, 1H). MS 331 (MH⁺).

Example 22b: 2-amino-6-(2-ethylbutoxy)benzonitrile

To a solution of 2-ethylbutan-1-ol (1.02 g, 10.0 mmol) in dry THF (60mL) was carefully added NaH (60% in mineral oil, 480 mg, 12.0 mmol) insmall portions at 0° C. under nitrogen.

The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. Tothis solution was added 2-amino-6-fluorobenzonitrile (1.36 g, 10.0mmol), and the reaction solution was stirred at 0° C.-RT for 2 hrs, andthen at 65° C. overnight under nitrogen. The reaction was cooled down toroom temperature then quenched with brine, and extracted with EtOAc(3×). The combined organic layers were washed with brine, dried overNa₂SO₄. Filtered and evaporated under reduced pressure. The residue waspurified by chromatography on silica gel (eluent: 20% EtOAc in hexanes)to give the title compound as colorless oil (1.29 g, 59%). ¹H NMR (400MHz, CDCl₃) δ 0.93 (t, J=8 Hz, 6H), 1.55-1.43 (m, 4H), 1.73-1.65 (m,1H), 3.90 (d, J=4 Hz, 2H), 4.10 (brs, 2H), 6.25 (d, J=8 Hz, 1H), 6.34(d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).

Example 23: 4-amino-5-(heptan-4-yloxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(heptan-4-yloxy)-2-methylquinoline-3-carboxylate (Example 23a)as a white solid (59%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.87 (t, J=7.2 Hz,6H), 1.49-1.25 (m, 4H), 1.84-1.60 (m 4H), 2.74 (s, 3H), 4.74-4.71 (m,1H), 7.07 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.4 Hz,1H), 8.82 (brs, 1H). MS 317 (MH⁺).

Example 23a: ethyl4-amino-5-(heptan-4-yloxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(heptan-4-yloxy)benzonitrile(Example 23b) and ethyl 3-oxobutanoate as a pale yellow solid (65%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.87 (t, J=7.2 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H),1.47-1.33 (m, 4H), 1.77-1.59 (m, 4H), 2.54 (s, 3H), 4.30 (q, J=7.2 Hz,2H), 4.67-4.64 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 7.19 (dd, J=0.8, 8.4 Hz,1H), 7.49 (t, J=8.0 Hz, 1H), 8.13 (brs, 2H). MS 345 (MH⁺).

Example 23b: 2-amino-6-(heptan-4-yloxy)benzonitrile

Prepared as in Example 22b from heptan-4-ol and2-amino-6-fluorobenzonitrile as a white solid (24%). ¹H NMR (400 MHz,CDCl₃) δ 0.92 (t, J=7.2 Hz, 6H), 1.55-1.31 (m, 8H), 3.88 (s, br, 1H),4.33-4.27 (m, 1H), 6.26 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 7.20(t, J=8.0 Hz, 1H).

Example 24:4-amino-5-(2-(isonicotinamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(isonicotinamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24a) as a white solid (67%). M.p.: 195-198° C. ¹H NMR (400 MHz,DMSO-d₆) δ 1.51 (s, 6H), 2.75 (s, 3H), 4.48 (s, 2H), 7.07 (d, J=8 Hz,1H), 7.31 (d, J=8 Hz, 1H), 7.67 (t, J=8 Hz, 1H), 7.70 (dd, J=1, 8 Hz,2H), 8.50 (s, 1H), 8.67 (dd, J=1, 8 Hz, 2H), 8.76 (brs, 1H), 12.19 (brs,1H), 12.85 (brs, 1H). MS 395 (MH⁺).

Example 24a: ethyl4-amino-5-(2-(isonicotinamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

To a solution of ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b, 1.0 g, 3.15 mmol) in dry DMF (20 mL) was addedisonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10mmol), HOBt (554 mg, 4.10 mmol), and triethylamine (414 mg, 4.10 mmol)at room temperature under nitrogen. After it was stirred at roomtemperature for 12 hrs, the reaction mixture was concentrated underreduced pressure. The residue was diluted with water, and extracted withEtOAc (3×). The aqueous layer was basified with 2N NaOH to pH 8 andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over MgSO₄, filtered, concentrated, and purified bychromatography on silica gel eluting with 10% MeOH in dichloromethane togive the title compound as a yellow solid (1.1 g, 83%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.29 (t, J=4 Hz, 3H), 1.51 (s, 6H), 2.94 (s, 3H), 4.28 (q,J=4 Hz, 2H), 4.42 (s, 2H), 6.93 (dd, J=1, 8 Hz, 1H), 7.24 (dd, J=1, 8Hz, 2H), 7.52 (t, J=8 Hz, 1H), 7.69 (dd, J=2, 4 Hz, 2H), 8.14 (s, 2H),8.37 (s, 1H), 8.67 (dd, J=2, 4 Hz, 2H). MS 423 (MH⁺).

Example 24b: ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from benzyl1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate (Example 24c)and ethyl 3-oxobutanoate as a yellow-brown solid (91%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.15 (s, 6H), 1.31 (t, J=4 Hz, 3H), 2.54 (s, 3H), 3.87 (s,2H), 4.31 (q, J=4 Hz, 2H), 6.85 (d, J=4 Hz, 1H), 7.21 (d, J=4 Hz, 1H),7.49 (t, J=8 Hz, 1H), 8.38 (brs, 2H). MS 318 (MH⁺).

Example 24c: benzyl1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate

To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile(Example 24d, 30.5 g, 148.6 mmol) in THF/H₂O (1:1, 400 mL) was addedNaHCO₃ (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl)carbonate (44.0 g, 176 mmol) at room temperature. The reaction wasstirred at room temperature for 4 h then the organic layer was separatedand the aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were washed with brine and dried over MgSO₄. Afterfiltration, the solvent was evaporated and the crude oil was purified bychromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give thetitle compound as yellow oil (44.8 g, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21(m, 6H). MS 340 (MH⁺).

Example 24d: 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile

To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) inanhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineraloil) in small portions at 0° C. under nitrogen. The mixture was stirredat 0° C. for 30 minutes and then stirred at room temperature for another30 minutes. The solution was cooled down to 0° C. again, and to thissolution was added dropwise a solution of 2-amino-6-fluorobenzonitrile(20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture wasthen refluxed overnight under nitrogen. The reaction mixture was cooleddown to room temperature and carefully quenched with aqueous NH₄Clsolution and extracted with ethyl acetate (3×). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude mixture was purified by chromatography on silicagel eluting with 10% MeOH in DCM to give the title compound as yellowsolid (23.4 g 71%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.08 (s, 6H), 3.15 (s,2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH⁺).

Example 25:4-amino-5-(2-(3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 25a) as a white solid (65%). M.p.: 195-198° C. ¹H NMR (400 MHz,DMSO-d₆) δ 1.48 (s, 6H), 2.75 (s, 3H), 4.47 (s, 2H), 6.87 (dt, J=8, 4Hz, 1H), 7.22-7.16 (m, 3H), 7.06 (d, J=8 Hz, 1H), 7.27 (d, J=8 Hz, 1H),7.67 (t, J=8 Hz, 1H), 8.08 (s, 1H), 8.84 (brs, 1H), 9.69 (s, 1H), 12.12(brs, 1H), 12.78 (brs, 1H). MS 410 (MH⁺).

Example 25a: ethyl4-amino-5-(2-(3-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate(Example 24b) and 3-hydroxybenzoic acid as a yellow-brown solid (64%).¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=4 Hz, 3H), 1.48 (s, 6H), 2.55 (s,3H), 4.30 (q, J=4 Hz, 2H), 4.41 (s, 2H), 6.85-6.88 (m, 1H), 6.92 (d, J=8Hz, 1H), 7.25-7.15 (m, 4H), 7.52 (t, J=8 Hz, 1H), 7.98 (s, 1H), 8.19 (s,2H), 9.59 (s, 1H). MS 438 (MH⁺).

Example 26:(S)-4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)-propoxy)-2-methylquinoline-3-carboxylate(Example 26a) as a white solid (53%). ¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.10 (m, 5H), 1.34-1.31 (m, 2H), 1.69-1.62 (m, 5H), 2.11-2.05 (m,1H), 2.69 (s, 3H), 3.93 (t, J=9.2 Hz, 1H), 4.13 (dd, J=4, 9.6 Hz, 1H),4.14-4.11 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.49(t, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H). MS 386 (MH⁺).

Example 26a: (S)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and cyclohexanecarboxylic acid as brown solid (28%). MS 414 (MH⁺).

Example 26b: (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)-carbamate (Example 26c) andethyl 3-oxobutanoate as brown solid. MS 304 (MH⁺).

Example 26c: (S)-benzyl (1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate

Prepared as in Example 24c from(S)-2-amino-6-(2-aminopropoxy)benzonitrile (Example 26d) as brown solid(86%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (d, J=6.4 Hz, 3H), 3.81 (d,J=8.4 Hz, 1H), 3.95-3.92 (m, 1H), 4.99 (s, 2H), 5.36 (s, 2H), 5.96 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.13 (t, J=8.4 Hz,1H), 7.44-7.38 (m, 5H). MS 326 (MH⁺).

Example 26d: (S)-2-amino-6-(2-aminopropoxy)benzonitrile

Prepared as in Example 24d from (S)-2-aminopropan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (73%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H),5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t,J=8.3 Hz, 1H). MS 192 (MH⁺).

Example 27:(S)-4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylic

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate(Example 27a) as an off-white solid (42%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31 (d, J=6.8 Hz, 3H), 2.66 (s, 3H), 4.14 (t, J=9.2 Hz, 1H), 4.28 (dd,J=3.6, 9.6 Hz, 1H), 4.70-4.55 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.26 (d,J=8.4 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.75 (dd, J=1.2, 6.0 Hz, 2H),8.71 (dd, J=1.2, 6.0 Hz, 2H), 8.95 (d, J=8.0 Hz, 1H). MS 409 (MH⁺).

Example 27a: (S)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and isonicotinic acid as brown solid (36%). MS 409 (MH⁺).

Example 28:(S)-4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 28a) as a white solid (58%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.28(d, J=7.2 Hz, 3H), 2.65 (s, 3H), 4.11 (t, J=8.8 Hz, 1H), 4.22 (dd,J=4.0, 10 Hz, 1H), 4.65-4.55 (m, 1H), 6.88 (d, J=8.0, 2H), 7.25-7.13 (m,4H), 7.48 (t, J=8.0 Hz, 1H), 8.49 (d, J=8.0, 1H), 9.93 (brs, 1H). MS 396(MH⁺).

Example 28a: (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 3-hydroxybenzoic acid as brown solid (41%). MS 424 (MH⁺).

Example 29:4-amino-5-(3-(cyclopentylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclopentylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 29a) as a white powder (74%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27(s, 6H), 1.36-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.72-1.78 (m, 2H), 2.78(s, 3H), 4.04 (m, 1H), 4.19 (s, 2H), 7.02 (d, J=8.0 Hz, 1H), 7.33 (d,J=8.0 Hz, 1H), 7.64-7.71 (m, 2H), 8.83 (brs, 1H), 12.25 (brs, 1H), 12.93(brs, 1H). MS 386 (MH⁺).

Example 29a: ethyl4-amino-5-(3-(cyclopentylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide(Example 29b) and ethyl 3-oxobutanoate as a bright yellow solid (62%).¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (s, 6H), 1.34 (t, J=8.0 Hz, 3H),1.40-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.74-1.77 (m, 2H), 2.57 (s, 3H),4.09 (q, J=4.0 Hz, 1H), 4.15 (s, 2H), 4.33 (q, J=8.0 Hz, 2H), 6.89 (d,J=4.0 Hz, 1H), 7.26 (dd, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.56 (s,1H), 8.09 (brs, 2H). MS 414 (MH⁺).

Example 29b:3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide

Prepared as in Example 22b fromN-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide (Example 29c) and2-amino-6-fluorobenzonitrile as a white solid (45%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.19 (s, 6H), 1.40-1.49 (m, 4H), 1.61-1.63 (m, 2H), 1.74-1.79(m, 2H), 3.95 (s, 2H), 4.03 (m, 1H), 5.98 (s, 2H), 6.19 (d, J=8.0 Hz,1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz,1H). MS 302 (MH⁺).

Example 29c: N-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide

Prepared as in Example 24a from hydroxypivalic acid and cyclopentylamine as an orange oil (32%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.00 (s, 6H),1.32-1.40 (m, 2H), 1.43-1.49 (m, 2H), 1.57-1.65 (m, 2H), 1.73-1.81 (m,2H), 3.34 (d, J=4.0 Hz, 2H), 3.98 (m, 1H), 4.87 (t, J=4.0 Hz, 1H), 7.22(d, J=4.0 Hz, 1H). MS 186 (MH⁺).

Example 30: 4-Amino-5-(cyclobutylmethoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(cyclobutylmethoxy)-2-methylquinoline-3-carboxylate (Example30a) as a white powder (51%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.84-1.99 (m,4H), 2.10-2.15 (m, 2H), 2.77 (s, 3H), 2.92 (m, 1H), 4.23 (d, J=8.0 Hz,2H), 7.05 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz,1H), 8.71 (brs, 1H), 12.23 (brs, 1H), 12.81 (brs, 1H). MS 287 (MH⁺).

Example 30a: ethyl4-amino-5-(cyclobutylmethoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cyclobutylmethoxy)benzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as an orange solid (26%). ¹H NMR (400 MHz, DMSO-d₆) δ1.32 (t, J=8.0 Hz, 3H), 1.83-1.90 (m, 4H), 2.10-2.13 (m, 2H), 2.59 (s,3H), 2.86 (m, 1H), 4.16 (d, J=4.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.90(d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.05(brs, 2H). MS 315 (MH⁺).

Example 31:4-amino-5-(2-(cyclopentanecarboxamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(cyclopentanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 31a) as an off-white solid (68%). ¹H NMR (400 MHz, DMSO-d₆) δ1.36 (s, 6H), 1.43-1.51 (m, 6H), 1.65-1.69 (m, 2H), 2.58 (m, 1H), 2.78(m, 3H), 4.37 (s, 2H), 7.04 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.68 (m,1H), 7.80 (s, 1H), 8.84 (brs, 1H), 12.42 (brs, 1H), 12.73 (brs, 1H). MS386 (MH⁺).

Example 31a: ethyl4-amino-5-(2-(cyclopentanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate(Example 24b) and cyclopentane carboxylic acid as a yellow solid (33%).¹H NMR (400 MHz, DMSO-d₆) δ 1.34 (t, J=4.0 Hz, 3H), 1.37 (s, 6H),1.42-1.53 (m, 6H), 1.64-1.69 (m, 2H), 2.58 (m, 1H), 2.62 (s, 3H), 4.32(s, 2H), 4.35 (m, 2H), 6.96 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.58 (m,1H), 7.66 (s, 1H), 8.41 (d, 2H). MS 414 (MH⁺).

Example 32: 4-Amino-5-(cycloheptyloxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(cycloheptyloxy)-2-methylquinoline-3-carboxylate (Example 32a)as a light yellow solid (34%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.65 (m,8H), 1.83-1.89 (m, 2H), 2.04-2.09 (m, 2H), 2.74 (s, 3H), 4.85 (m, 1H),7.03 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H),8.82 (brs, 1H), 12.24 (brs, 1H), 12.64 (brs, 1H). MS 315 (MH⁺).

Example 32a: ethyl4-amino-5-(cycloheptyloxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cycloheptyloxy)benzonitrile(Example 32b) and ethyl 3-oxobutanoate as a bright yellow solid (72%).¹H NMR (400 MHz, DMSO-d₆) δ 1.32 (t, J=8.0 Hz, 3H), 1.49-1.65 (m, 8H),1.78-1.87 (m, 2H), 2.04-2.10 (m, 2H), 2.53 (s, 3H). 4.31 (q, J=8.0 Hz,2H), 4.79 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.49(t, J=8.0 Hz, 1H), 8.14 (brs, 2H). MS 343 (MH⁺).

Example 32b: 2-amino-6-(cycloheptyloxy)benzonitrile

Prepared as in Example 22b from cycloheptanol and2-amino-6-fluorobenzonitrile as yellow oil (11%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.42-1.71 (m, 10H), 1.88-1.93 (m, 2H), 4.56 (m, 1H), 5.95 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz,1H). MS 231 (MH⁺).

Example 33: 4-Amino-2-methyl-5-(3-phenoxypropoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(3-phenoxypropoxy)quinoline-3-carboxylate (Example33a) as a yellow solid (90%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.35 (m, 2H),2.77 (s, 3H), 4.19 (t, J=4.0 Hz, 2H), 4.42 (t, J=4.0 Hz, 2H), 6.91-6.96(m, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.26-7.30 (m, 3H), 7.70 (t, J=8.0 Hz,1H), 8.96 (brs, 1H), 12.24 (brs, 1H), 12.75 (brs, 1H). MS 353 (MH⁺).

Example 33a: ethyl4-amino-2-methyl-5-(3-phenoxypropoxy)quinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(3-phenoxypropoxy)benzonitrile(Example 33b) and ethyl 3-oxobutanoate as a yellow solid (47%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.33 (t, J=8.0 Hz, 3H), 2.34 (m, 2H), 2.57 (s, 3H),4.19 (t, J=4.0 Hz, 2H), 4.33 (q, J=8.0 Hz, 2H), 4.37 (t, J=4.0 Hz, 2H),6.91-6.97 (m, 4H), 7.24-7.29 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 8.17 (s,2H). MS 381 (MH⁺).

Example 33b: 2-amino-6-(3-phenoxypropoxy)benzonitrile

Prepared as in Example 22b from 3-phenoxy-1-propanol and2-amino-6-fluorobenzonitrile as a yellow oil (93%). ¹H NMR (400 MHz,DMSO-d₆) δ 2.14 (m, 2H), 4.10-4.16 (m, 4H), 5.98 (s, 2H), 6.23 (d, J=8.0Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.89-6.94 (m, 5H), 7.16 (t, J=8.0 Hz,1H).

Example 34:44-Amino-5-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 34a) as an orange powder (23%). ¹H NMR (400 MHz, DMSO-d₆) δ1.24 (brs, 2H), 1.79-1.88 (m, 2H), 2.29 (m, 1H), 2.77 (s, 3H), 3.07(brs, 2H), 3.65 (brs, 1H), 4.17 (d, J=8.0 Hz, 2H), 4.50 (brs, 1H),6.74-6.83 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.29(d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 8.74 (brs, 1H), 9.75 (s, 1H),12.25 (brs, 1H), 12.71 (brs, 1H). MS 436 (MH⁺).

Example 34a: ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)benzonitrile(Example 34b) and ethyl 3-oxobutanoate as a yellow solid (49%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.24 (m, 2H), 1.31 (t, J=4.0 Hz, 3H), 1.77-1.89 (m,2H), 2.22 (brs, 1H), 2.55 (s, 3H), 2.79 (brs, 1H), 3.04 (brs, 1H), 3.64(brs, 1H), 4.10 (m, 2H), 4.32 (q, J=8.0 Hz, 2H), 4.49 (brs, 1H),6.71-6.82 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 7.19-7.25 (m, 2H), 7.52 (t,J=8.0 Hz, 1H), 8.06 (brs, 2H), 9.64 (s, 1H). MS 464 (MH⁺).

Example 34b:2-amino-6-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 24a from2-amino-6-(piperidin-4-ylmethoxy)benzonitrile (Example 34c) and3-hydroxybenzoic acid as an orange glass (66%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.29 (m, 2H), 1.66-1.92 (m, 2H), 2.06 (m, 1H), 2.80 (brs,1H), 3.05 (brs, 1H), 3.62 (brs, 1H), 3.91 (d, J=8.0 Hz, 2H), 4.49 (brs,1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H),6.72-6.83 (m, 3H), 7.15-7.24 (m, 2H), 9.65 (s, 1H). MS 352 (MH⁺).

Example 34c: 2-amino-6-(piperidin-4-ylmethoxy)benzonitrile

To a solution of tert-butyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 34d,1.33 g, 4.0 mmol) in EtOAc (20 mL) was added dropwise aqueous HClsolution (12 N, 6.6 mL) at 0° C. The reaction mixture was stirred atroom temperature overnight. The solvent was removed under reducedpressure to give the title compound (100%) as a brown solid, which ispure enough and used directly in the next step without furtherpurification. MS 232 (MH⁺).

Example 34d: 2 tert-butyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 22b from N-Boc-4-piperidinemethanol and2-amino-6-fluoro-benzonitrile as an off-white solid (37%). ¹H NMR (400MHz, DMSO-d₆) δ 1.15-1.21 (m, 2H), 1.40 (s, 9H), 1.74 (m, 2H), 1.99(brs, 1H), 2.74 (brs, 2H), 3.87 (d, J=4.0 Hz, 2H), 3.96 (m, 2H), 5.99(s, 2H), 6.21 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0Hz, 1H). MS 232 (MH⁺-Boc).

Example 35:4-Amino-5-((1-butyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 ethyl4-amino-5-((1-butyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 35a) as a white solid (61%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.87(t, J=8.0 Hz, 3H), 1.05-1.22 (m, 2H), 1.50 (m, 2H), 1.80 (m, 2H),2.24-2.31 (m, 3H), 2.65 (s, 3H), 3.02 (2H), 3.88-3.92 (m, 1H), 4.11 (m,2H), 4.44 (m, 1H), 7.05 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.69 (m, 1H),8.76 (brs, 1H), 12.33 (brs, 1H), 12.65 (brs, 1H). MS 386 (MH⁺).

Example 35a: ethyl4-amino-5-((1-butyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-2-methyl-5-(piperidin-4-ylmethoxy)-quinoline-3-carboxylate(Example 35b) and butyric acid as a yellow oil (50%). MS 414 (MH⁺).

Example 35b: ethyl4-amino-2-methyl-5-(piperidin-4-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from benzyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 35c)and ethyl 3-oxobutanoate as an orange solid (25%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.29-1.37 (m, 5H), 1.77-1.80 (m, 2H), 2.07 (brs, 1H), 2.53(s, 3H), 2.55-2.65 (m, 3H), 3.06-3.09 (m, 2H), 4.06 (d, J=8.0 Hz, 2H),4.32 (q, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H),7.51 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 344 (MH⁺).

Example 35c: 4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 22b from 1-N-Cbz-4-(hydroxymethyl)piperidine and2-amino-6-fluoro-benzonitrile as a yellow oil (18%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.20-1.25 (m, 2H), 1.75-1.78 (m, 2H), 1.96 (brs, 1H), 3.88(d, J=8.0 Hz, 2H), 3.99-4.04 (m, 4H), 5.07 (s, 2H), 5.99 (s, 2H), 6.21(d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H),7.29-7.40 (m, 5H). MS 366 (MH⁺).

Example 36: 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylicAcid

To a solution of ethyl4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a,110 g, 0.335 mol) in EtOH (450 mL) was added a solution of NaOH (33.5 g,0.837 mol) in water (200 mL) at room temperature. The reaction mixturewas then refluxed overnight. The reaction solution was cooled down to 0°C. and carefully neutralized with 4N HCl to pH 7. The resultant solutionwas concentrated under reduced pressure to remove most of the EtOH. Theprecipitate was collected by filtration, and re-dissolved in EtOH (4 L)at 65° C. and treated with activated charcoal (5 g) for 0.5 h. Thecharcoal was removed by filtration over celite, and the filtrate wasconcentrated. The precipitate was collected by filtration, washed withcold water, and dried under vacuum at 60° C. overnight to give the titlecompound as a white solid (100 g, 99%). M.p.: 220.0-221.5° C. ¹H NMR(400 MHz, DMSO-d₆) δ 1.28-1.72 (m, 8H), 2.00-2.04 (m, 2H), 2.75 (s, 3H),4.69-4.71 (m, 1H), 7.10-7.12 (d, J=8.0 Hz, 1H), 7.24-7.26 (d, J=8.0 Hz,1H), 7.65 (t, J=8.0 Hz, 1H), 12.80 (brs, 1H). MS 301 (MH⁺). ElementalAnalysis Calculated (Found) for C₁₇H₂₀N₂O₃: C, 67.98% (67.74%); H, 6.71%(7.01%); N, 9.33% (9.40%).

Example 36a: ethyl4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate

A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydroustoluene (200 mL) was added to a solution of2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b, 49.8 g, 0.230 mol)in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottomflask sitting in an oil bath at room temperature. SnCl₄ (53.9 mL, 0.461mol) was added slowly over a period of approximately 1 h. The oil bathtemperature was then raised to 110° C. and the reaction mixture wasstirred at that temperature for 2.5 h. It was then cooled down to 5° C.,still under nitrogen, and the toluene was decanted away from theimmiscible viscous oil at the bottom of the flask. The viscous oil wasfurther concentrated under vacuum at 60° C., re-dissolved in boilingethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. Thesolution was diluted with more EtOAc (1.5 L), cooled down to −15° C.,and neutralized with NaOH (3 N, 500 mL). The organic layer wasseparated, and the aqueous emulsion was extracted once more with ethylacetate. The insoluble tin salts were filtered out from the aqueouslayer, then both the salts and aqueous filtrate were washed once morewith ethyl acetate. The combined organic layers were dried over MgSO₄,concentrated, and passed through a silica column using 0% to 60% ethylacetate in hexanes. The product was purified by recrystallization fromEtOAc to give the title compound as an off-white solid (64.3 g, 85%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m,2H), 1.51-1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s,3H), 4.28-4.33 (q, J=6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J=7.6 Hz,1H), 7.19-7.21 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.15 (brs,2H). MS 329 (MH⁺).

Example 36b: 2-amino-6-(cyclohexyloxy)benzonitrile

To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in smallportions at 0° C. under nitrogen. The mixture was stirred at roomtemperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at roomtemperature. The reaction mixture was heated to reflux overnight thencooled to room temperature and most of the THF removed under reducedpressure. Ice water (100 mL) was added to the concentrated reactionmixture followed by EtOAc (500 mL). The organic layer was separated andsuccessively washed with water and brine, dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified bychromatography on silica gel eluting with 25-30% EtOAc in hexanes togive 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H),1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m,2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (MH⁺).

Example 36b: 2-amino-6-(cyclohexyloxy)benzonitrile

Alternative Method a):

To a solution of 2-(cyclohexyloxy)-6-nitrobenzonitrile (Example 36c,50.0 g, 0.20 mol) in THF/AcOH (1:1 by volume, 500 mL) was added ironpowder (34.0 g, 0.61 mol) in one portion at room temperature undernitrogen. The reaction mixture was refluxed for 40 min under nitrogenand cooled down to room temperature and EtOAc (2 L) was added. Theprecipitate that formed was filtered off and washed with EtOAc. Theorganic layer was separated and washed successively with water (2×300mL), aqueous NaOH (1.0 N, 2×300 mL), saturated Na₂CO₃ solution (300 mL),brine (300 mL), dried over Na₂SO₄ filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica geleluting with 25% EtOAc in hexanes to give2-amino-6-(cyclohexyloxy)benzonitrile as a pale yellow oil (45.0 g,94%), which solidified after storage overnight at room temperature.

Alternative Method b):

A 3-L 3-neck round bottom flask was first purged with nitrogen. 10% Pd/C(2.81 g) was then added under nitrogen, followed successively by2-(cyclohexyloxy)-6-nitrobenzonitrile (Example 36c, 43.2 g, 0.175 mol),anhydrous methanol (389 mL), and acetic acid (80.4 mL). A refluxcondenser, a dropping funnel containing a solution of ammonium formate(49.8 g, 0.790 mol) in anhydrous methanol (498 mL), thermometer,nitrogen inlet and nitrogen outlet were attached. Ammonium formatesolution (75 mL) was added at room temperature, then the reaction wasslowly heated to a maximum of 42° C. The mixture was monitored carefullyuntil initiation of the reaction was observed (an evolution of gasoccurred with roughly a 10° C. exotherm). Initiation of the reactionoften took up to 40 minutes before starting. The remaining of theammonium formate solution was then added at a rate which maintained aninternal reaction temperature of 40° C. to 48° C. After the addition wascomplete, the reaction mixture was stirred for another 10 minutes at 45°C., then cooled down to room temperature. The Pd/C was filtered outusing a Teflon filter, and the solvent was evaporated. Ice water (1 L)was added to the residue, then the water was decanted and discarded. Theresidue was dissolved in diethyl ether, washed with water, thensaturated sodium bicarbonate solution, then dried with magnesium sulfateand concentrated. The product was then purified on silica gel usingisocratic DCM to give the product as a yellow oil (31.5 g, 83%).

Example 36c: 2-(cyclohexyloxy)-6-nitrobenzonitrile

To a solution of cyclohexanol (46.8 grams, 0.467 mol) in anhydrous THF(1 L) was added sodium hydride (20.3 grams, 0.508 mol) at −40° C. undernitrogen. The reaction mixture was allowed to warm slowly to roomtemperature and stir for another 1 hour. It was then cooled down to −55°C. and 2,6-dinitrobenzonitrile (78.4 g, 0.406 mol) was added. Thereaction was stirred at room temperature overnight, then cooled down to−20° C., and citric acid (23.4 grams, 0.122 mol) was added. The mixturewas then poured into ice water (5 L) which contained citric acid (7.8 g,0.041 mol), stirred for 15 minutes, and the precipitated product wascollected by filtration. The crude product was recrystallized fromisopropanol (750 mL, heated to boiling, then cooled down to 0° C.),filtered, washed with isopropanol (300 mL), then air dried to give 84.4g yellow solid. The solid was dissolved in dichloromethane (169 mL) andfiltered through a plug of alumina to give the title compound as a paleyellow solid (83.2 g, 83.2%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.4 (m, 4H),1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 4.75 (m, 1H), 7.79 (dd, J=2.0,8.0 Hz, 1H), 7.84-7.91 (m, 2H).

Example 37:4-amino-5-(2-(cyclohexanecarboxamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(cyclohexanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 37a) as a white powder (78%). ¹H NMR (400 MHz, DMSO-d₆) δ1.11-1.22 (m, 5H), 1.33 (s, 6H), 1.56-1.62 (m, 5H), 2.14 (m, 1H), 2.78(s, 3H), 4.34 (s, 2H), 7.01 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H),7.66 (t, J=8.4 Hz, 1H), 7.74 (s, 1H). MS 400 (MH⁺).

Example 37a: ethyl4-amino-5-(2-(cyclohexanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexanecarboxamide(Example 37b) and ethyl 3-oxobutanoate as a bright yellow solid (55%).MS 428 (MH⁺).

Example 37b:N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexanecarboxamide

Prepared as in Example 22b fromN-(1-hydroxy-2-methylpropan-2-yl)cyclohexanecarboxamide (Example 37c)and 2-amino-6-fluorobenzonitrile as an off-white solid (29%). MS 316(MH⁺).

Example 37c: N-(1-hydroxy-2-methylpropan-2-yl)cyclohexanecarboxamide

Prepared as in Example 24a from cyclohexanecarboxylic acid and2-amino-2-methylpropan-1-ol as a colorless oil (15%). MS 200 (MH⁺).

Example 38:4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

To a solution of4-amino-5-(2-(3-(2-(benzyloxy)ethoxy)-5-methoxybenzamido)-2-methy-propoxy)-2-methylquinoline-3-carboxylicacid (Example 38a, 237 mg, 0.5 mmol) in EtOH/EtOAc (1:1, 20 mL) wasadded 10% Pd/C (wet, 50 mg). The suspension was then stirred under anatmosphere of hydrogen at room temperature overnight. The Pd/C wasfiltered off, and the filtrate was concentrated. The residue waspurified by HPLC (eluent: 10-100% MeOH in H₂O) to give the titlecompound as an off-white solid (152 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆)δ 1.49 (s, 6H), 2.75 (s, 3H), 3.68 (t, J=5.2 Hz, 2H), 3.73 (s, 3H), 3.99(t, J=5.2 Hz, 1H), 4.47 (s, 2H), 6.57 (s, 1H), 6.88 (s, 1H), 6.96 (s,1H), 7.06 (d, J=7.6 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.67 (t, J=8 Hz, 1H),8.14 (s, 1H). MS 484 (MH⁺).

Example 38a:4-amino-5-(2-(3-(2-(benzyloxy)ethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 38b) as a white powder (95%). MS 574 (MH⁺).

Example 38b: ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoic acid (Example39c) as a pale-brown solid (90%). MS 602 (MH⁺).

Example 38c: 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoic

Prepared as in Example 1 from methyl3-(2-(benzyloxy)ethoxy)-5-methoxybenzoate (Example 38d) as a white solid(64%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.83 (s, 3H), 3.84 (t, J=4.8 Hz, 2H),4.18 (t, J=4.8 Hz, 2H), 4.65 (s, 2H), 6.74 (s, 1H), 7.25-7.37 (m, 7H).

Example 38d: methyl 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoate

To a solution of methyl 3-hydroxy-5-methoxybenzoate (Chakraporty, T. K.and Reddy, G. V. J. Org. Chem, 57, 1992, 5462) (3.3 g, 18.1 mmol) in dryDMF (30 mL) was added K₂CO₃ (6.3 g, 45.3 mmol) at room temperature. Thereaction was stirred at room temperature for 10 minutes then((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and themixture stirred at 160° C. for 2 hrs. The reaction was cooled down toroom temperature and diluted with EtOAc, washed with water and brine,and dried over MgSO₄, filtered and concentrated to give the crudeproduct (90%) which was used in the next step without furtherpurification.

Example 39:4-amino-5-((2-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((2-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 39a) as a white powder (90%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.83(d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.42 (m, 3H), 1.65 (m, 4H),1.96 (m, 1H), 2.40 (m, 1H), 2.76 (s, 3H), 4.13 (m, 1H), 4.99 (m, 1H),7.07 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.63 (t, J=8 hz, 1H),7.93 (d, J=7.6 Hz, 1H). MS 386 (MH⁺).

Example 39a: ethyl4-amino-5-((2-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-(2-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide (Example 39b) andethyl 3-oxobutanoate as a yellow solid (63%). MS 414 (MH⁺).

Example 39b: N-(2-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide

Prepared as in Example 22b from N-(2-hydroxycyclohexyl)isobutyramide(Example 39c) and 2-amino-6-fluorobenzonitrile as a brown solid (70%).MS 302 (MH⁺).

Example 39c: N-(2-hydroxycyclohexyl)isobutyramide

Prepared as in Example 24a from isobutyric acid and 2-aminocyclohexanolas a colorless oil (53%). MS 186 (MH⁺).

Example 40:4-amino-5-((4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 40a) as a white powder (87%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.97(d, J=7.2 Hz, 6H), 1.34-1.37 (m, 2H), 1.65-1.68 (m, 2H), 1.81-1.84 (m,2H), 2.13-2.16 (m, 2H), 2.33 (m, 1H), 2.75 (s, 3H), 3.58 (m, 1H), 4.84(m, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.65 (d, J=7.6Hz, 2H). MS 386 (MH⁺).

Example 40a: ethyl4-amino-5-((4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-(4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide (Example 40b) andethyl 3-oxobutanoate as a yellow solid (57%). MS 414 (MH⁺).

Example 40b: N-(4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide

Prepared as in Example 22b from N-(4-hydroxycyclohexyl)isobutyramide(Example 40c) and 2-amino-6-fluorobenzonitrile as an off-white solid(99%). MS 302 (MH⁺).

Example 40c: N-(4-hydroxycyclohexyl)isobutyramide

Prepared as in Example 24a from isobutyric acid and 4-aminocyclohexanolas a colorless oil (44%). MS 186 (MH⁺).

Example 41: 4-amino-5-isobutoxy-2-methylquinoline-3-carboxylic Acid

To a solution of ethyl4-amino-5-isobutoxy-2-methylquinoline-3-carboxylate (Example 41a, 18.0g, 59.53 mmol) in EtOH (150 mL) was added aqueous NaOH solution (3 N, 50mL) and the reaction mixture was refluxed overnight. It was then cooleddown to room temperature and the solution was filtered to remove anypossible solid residue. The filtrate was carefully neutralized with 6NHCl to pH 7 at 0° C. The resultant precipitate was collected byfiltration, washed with water, re-dissolved in EtOH (700 mL) and water(20 mL), and treated with activated charcoal (650 mg) at 70° C. for 0.5h. The charcoal was removed by filtration, and the filtrate wasconcentrated and stored at 4° C. overnight. The resulting precipitatewas collected by filtration, washed with cold H₂O, and dried undervacuum at 60° C. overnight to give the title compound as a white solid(4.24 g, 26%). M.p.: 203.7° C. ¹H NMR (400 MHz, DMSO-d₆) δ 1.01-1.02 (m,6H), 2.19-2.24 (m, 1H), 2.77 (s, 3H), 4.05 (d, J=6.4 Hz, 2H), 7.08 (d,J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.9 (brs,1H), 11.45 (brs, 1H), 13.2 (brs, 1H). MS 275 (MH⁺). Elemental AnalysisCalculated (Found) for C₁₅H₁₈N₂O₃.0.75H₂O: C, 62.59% (62.23%); H, 6.83%(7.25%); N, 9.76% (9.73%).

Example 41a: ethyl 4-amino-5-isobutoxy-2-methylquinoline-3-carboxylate

To a solution of 2-amino-6-isobutoxybenzonitrile (Example 41b, 16.4 g,86.32 mmol) and ethyl acetoacetate (10.9 mL, 86.32 mmol) in anhydroustoluene (200 mL) was added SnCl₄ (19.9 mL, 172.63 mmol) over a period of15 minutes at room temperature under nitrogen. The stirred reactionmixture was then refluxed for 3.5 h under nitrogen. After it was cooleddown to room temperature, the reaction solution was concentrated toremove most of the solvent under reduced pressure. The residue wasre-dissolved in EtOAc (3 L) and carefully neutralized to pH 8 withaqueous NaOH solution (6.0 N, ˜110 mL) at 0° C. The resultant mixturewas stirred at room temperature overnight. The precipitate was filteredoff, and the organic layer was separated and washed with brine (400 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel eluting with 50%EtOAc in hexanes to give the title compound as a white solid (18.0 g,69%). MS 303 (MH⁺).

Example 41b: 2-amino-6-isobutoxybenzonitrile

To a solution of 2-isobutoxy-6-nitrobenzonitrile (Example 41c, 34.3 g,0.156 mol) in AcOH/THF (1:1 by volume, 250 mL) was added iron powder(17.36 g, 0.311 mol) in one portion. The stirred suspension was heatedto reflux for 30 minutes. After it was cooled down to room temperature,the reaction solution was diluted with EtOAc (1 L). The solid wasremoved by filtration, and the filtrate was washed subsequently withwater (300 mL×2), 1N NaOH (300 mL), saturated Na₂CO₃ aqueous solution(300 mL), brine (300 mL), and dried over Na₂SO₄. After evaporation ofthe solvent, the residue was purified by chromatography on silica geleluting with 20% EtOAc in hexanes to give the title compound as a yellowoil (16.4 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.96 (d, J=6.8 Hz, 6H),1.96-2.02 (m, 1H), 3.75 (d, J=6.4 Hz, 2H), 5.96 (s, 2H), 6.17 (d, J=8.4Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 1H). MS 191 (MH⁺).

Example 41b Alternative Procedure: 2-amino-6-isobutoxybenzonitrile

Sodium hydride (60% suspension in oil, 25.0 g, 0.625 mol) was suspendedin anhydrous THF (1000 mL) under nitrogen and heated to an internaltemperature of 40° C. to 45° C. 2-methylpropan-1-ol (61.2 mL, 0.661 mol)was then added slowly and portionwise. The mixture was heated at 40° C.to 45° C. for 1 hour, then cooled to 35° C. 2-amino-6-fluorobenzonitrile(50.0 g, 0.367 mol) was added and refluxed for 21 hours. The mixture wascooled to r.t., then ice (250 g), ice water (750 mL), and hexanes (1000mL) was added. Insoluble solids were filtered out and the organic layerwas separated. The aqueous layer was extracted once more with a mixtureof diethyl ether (250 mL) and hexanes (250 mL). The combined organiclayer was washed twice with a solution of citric acid (53 g) in water(500 mL), then washed with 80% brine (300 mL), then dried with magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas dissolved in methanol (500 mL), and the immiscible oil carriedthrough from the sodium hydride suspension was separated off in aseparatory funnel. The solvent was evaporated under vacuum, and theresidue was washed with hexanes (250 mL), after which the product2-amino-6-isobutoxybenzonitrile was obtained as a viscous oil (46 grams,yield: 66%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=8.0 Hz, 1H), 6.33(d, J=8.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 3.75 (d, J=7.2Hz, 2H), 2.00 (m, 1H), 0.97 (d, J=6.8 Hz, 6H) ppm. MS 191 (MH⁺).

Example 41c: 2-isobutoxy-6-nitrobenzonitrile

To a solution of 2-methylpropan-1-ol (9.6 mL, 0.104 mol) in anhydrousTHF (200 mL) was added NaH (60% in mineral oil, 4.565 g, 0.114 mol) insmall portions at 0° C. under N₂. After it was stirred at roomtemperature for 30 min, the reaction mixture was cooled down to −70° C.and 2,6-dinitrobenzonitrile (20.0 g, 0.104 mol) was added portionwise.After the addition was complete, the reaction mixture was stirred at−70° C.-RT overnight, then poured into ice water (600 mL). The resultantprecipitate was collected by filtration and rinsed with water, hexane,and air dried to provide 2-isobutoxy-6-nitrobenzonitrile as a lightyellow solid (34.3 g, 100%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.0 (d, J=6.8Hz, 6H), 2.04-2.11 (m, 1H), 4.02 (d, J=6.8 Hz, 2H), 7.69-7.71 (m, 1H),7.84-7.90 (m, 2H). MS 221 (MH⁺).

Example 42: 4-amino-5-isopropoxy-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-5-isopropoxy-2-methylquinoline-3-carboxylate (Example 42a) as awhite solid (71%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.4 (d, J=6.4 Hz, 6H),2.73 (s, 3H), 4.87-4.93 (m, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.60 (t, J=8.4 Hz, 1H). MS 261 (MH⁺).

Example 42a: ethyl 4-amino-5-isopropoxy-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-isopropoxybenzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as an off-white solid (32%). ¹H NMR (400 MHz, DMSO-d₆) δ1.32 (t, J=7.6 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 2.54 (s, 3H), 4.3 (q,J=7.2 Hz, 2H), 4.83-4.89 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 8.14 (s, 2H). MS 289 (MH⁺).

Example 43:4-amino-5-((1-(hydroxymethyl)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-(hydroxymethyl)cyclohexyl)-methoxy)-2-methylquinoline-3-carboxylate(Example 43a) as an off-white solid (49%). ¹H NMR (400 MHz, DMSO-d₆) δ1.37-1.48 (m, 10H), 2.75 (s, 3H), 3.50 (s, 2H), 4.03 (s, 2H), 5.08 (brs,1H), 7.06 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.66 (t, J=8.4 Hz,1H), 9.39 (brs, 1H), 12.17 (brs, 1H), 12.74 (brs, 1H). MS 345 (MH⁺).

Example 43a: ethyl4-amino-5-((1-(hydroxymethyl)cyclohexyl)methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 2a from(1-((3-amino-2-cyanophenoxy)methyl)cyclohexyl)-methyl acetate(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as an off-white solid (60%). MS 373 (MH⁺).

Example 44:4-amino-5-(2-(3,5-dihydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 44a) as a white solid (73%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.46(s, 6H), 2.75 (s, 3H), 4.44 (s, 2H), 6.3-6.31 (m, 1H), 6.61 (s, 2H),7.04 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H),7.98 (s, 1H), 8.79 (brs, 1H), 9.48 (s, 2H). MS 426 (MH⁺).

Example 44a: ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3,5-dihydroxybenzoic acid as a yellow-brown solid(15%). MS 454 (MH⁺).

Example 45:4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)-oxy)-2-methylquinoline-3-carboxylate(Example 45a) as a white powder (71%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.01(d, J=6.4 Hz, 6H), 1.59-1.68 (m, 6H), 2.06-2.09 (m, 2H), 2.2-2.22 (m,1H), 2.76 (s, 3H), 3.77-3.83 (m, 1H), 4.96 (s, 1H), 7.06 (d, J=8.0 Hz,1H), 7.26 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.4 Hz,1H), 8.79 (brs, 1H), 12.84 (brs, 2H). MS 386 (MH⁺).

Example 45a: ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)oxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 2a from4-(3-amino-2-cyanophenoxy)-N-isopropylcyclohexanecarboxamide (Example45b) and ethyl 3-oxobutanoate as a yellow solid (56%). MS 414 (MH⁺).

Example 45b:4-(3-amino-2-cyanophenoxy)-N-isopropylcyclohexanecarboxamide

Prepared as in Example 22b from4-hydroxy-N-isopropylcyclohexanecarboxamide (Example 45c) and2-amino-6-fluorobenzonitrile as an off-white solid (17%). ¹H NMR (400MHz, DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H), 1.47-1.57 (m, 4H), 1.67-1.77 (m,2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 1H), 3.75-3.84 (m, 1H), 4.57 (brs,1H), 5.93 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.0 Hz, 1H), 7.13(t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 302 (MH⁺).

Example 45c: 4-hydroxy-N-isopropylcyclohexanecarboxamide

Prepared as in Example 24a from 4-hydroxycyclohexanecarboxylic acid andpropan-2-amine as a colorless oil (68%). MS 186 (MH⁺).

Example 46:4-amino-5-(3-((3-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-((3-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 46a) as a white powder (58%). M.p.: 172-174° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.31 (s, 6H), 2.76 (s, 3H), 3.53 (s, 3H), 4.21 (s, 2H),4.27 (d, J=5.6 Hz, 2H), 6.64 (dd, J=8.0, 2.4 Hz, 1H), 6.69 (m, 1H), 6.72(d, J=8.0 Hz, 1H), 6.98-7.10 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.66 (t,J=8.0 Hz, 1H), 8.47 (t, J=5.6 Hz, 1H), 8.77 (brs, 1H), 12.26 (brs, 1H),12.79 (brs, 1H). MS 438 (MH⁺).

Example 46a: ethyl4-amino-5-(3-((3-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide(Example 46b) and ethyl 3-oxobutanoate as a yellow solid (42%). MS 466(MH⁺).

Example 46b:3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 22b from3-hydroxy-N-(3-methoxybenzyl)-2,2-dimethylpropanamide (Example 46c) and2-amino-6-fluorobenzonitrile as a white solid (41%). MS 354 (MH⁺).

Example 46c: 3-hydroxy-N-(3-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 24a from 3-hydroxy-2,2-dimethylpropanoic acid and(3-methoxyphenyl)methanamine as an orange oil (41%). MS 238 (MH⁺).

Example 47:4-amino-5-(3-(cyclohexylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclohexylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 47a) as an off-white solid (13%). MS 400 (MH⁺).

Example 47a: ethyl4-amino-5-(3-(cyclohexylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclohexanamine as a yellow-brown solid (46%). MS428 (MH⁺).

Example 47b:3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicAcid

Prepared as in Example 2a from benzyl3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropanoate (Example 47c) andethyl 3-oxobutanoate as a brown solid (80%). MS 192 (MH⁺).

Example 47c: 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropanoate

To a solution of benzyl3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropanoate (Example 47d, 200 mg,0.56 mmol) in AcOH (5 mL) was added iron powder (158 mg, 2.82 mmol) atroom temperature. The reaction mixture was then stirred at 90° C. for 1h. The reaction mixture was was cooled to room temperature then dilutedwith AcOEt. The precipitate was filtered off and the filtrate wassuccessively washed with 1 N NaOH and brine, then dried over Na₂SO₄,filtered and evaporated. The residue was purified by chromatography onsilica gel (eluent: 40% EtOAc in hexanes) to give a title compound as acolorless oil (187 mg, 100%). MS 325 (MH⁺).

Example 47d: benzyl 3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropanoate

To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. etal. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF(200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol)in small portions at 0° C. under nitrogen. The reaction mixture wasstirred at 0° C. under nitrogen for 2 hrs. To this solution was added2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solutionwas stirred at 0° C.-RT under nitrogen overnight. The reaction mixturewas quenched with brine, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄. Afterevaporation of the solvent, the residue was purified by chromatographyon silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the titlecompound as a brown solid (10.0 g, 87%). MS 355 (MH⁺).

Example 48:4-amino-5-(3-(cycloheptylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cycloheptylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 48a) as an off-white solid (12%). MS 414 (MH⁺).

Example 48a: ethyl4-amino-5-(3-(cycloheptylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cycloheptanamine as a brown solid (43%). MS 456(MH⁺).

Example 49:4-amino-5-(3-(cyclooctylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclooctylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 49a) as an off-white solid (11%). MS 428 (MH⁺).

Example 49a: ethyl4-amino-5-(3-(cyclooctylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclooctanamine as a brown solid (46%). MS 456(MH⁺).

Example 50:4-amino-5-(3-((3-hydroxy-2,2-dimethylpropyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-((3-hydroxy-2,2-dimethylpropyl)-amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 50a) as an off-white solid (87%). ¹H NMR (400 MHz, DMSO-d₆) δ0.71 (s, 6H), 1.28 (s, 6H), 2.74 (s, 3H), 2.97 (d, J=6.0 Hz, 2H), 3.0(s, 2H), 4.57 (brs, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H),7.65 (t, J=8.4 Hz, 1H), 7.77 (t, J=6.4 Hz, 1H), 8.78 (brs, 1H), 12.04(brs, 1H), 12.82 (brs, 1H). MS 404 (MH⁺).

Example 50a: ethyl4-amino-5-(3-((3-hydroxy-2,2-dimethylpropyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and 3-amino-2,2-dimethylpropan-1-ol as a brown solid(40%). MS 432 (MH⁺).

Example 51:4-amino-5-(3-(chroman-4-ylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(chroman-4-ylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 51a) as an off-white solid (80%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31 (d, J=4.0 Hz, 6H), 1.80-2.00 (m, 2H), 2.76 (s, 3H), 4.05-4.19 (m,2H), 4.24 (s, 2H), 5.10 (q, J=6.8 Hz, 1H), 6.51 (t, J=7.6 Hz, 1H), 6.89(d, J=8.4 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.01 (dd, J=15.0, 8.4 Hz,2H), 7.30 (d, J=8.8 Hz, 1H), 7.66 (t, J=8.4 Hz, 1H), 8.26 (d, J=8.8 Hz,1H), 8.77 (brs, 1H), 12.31 (brs, 1H), 12.86 (brs, 1H). MS 450 (MH⁺).

Example 51a: ethyl4-amino-5-(3-(chroman-4-ylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and chroman-4-amine (Lu, Y. et al. PCT Int. Appl.2008, WO 2008043019) as a brown solid (37%). MS 478 (MH⁺).

Example 52:4-amino-5-(3-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 52a) as an off-white solid (69%). ¹H NMR (400 MHz, DMSO-d₆) δ1.30 (d, J=4.0 Hz, 6H), 1.52-1.87 (m, 4H), 2.75 (s, 3H), 4.22 (s, 2H),4.95-5.05 (m, 1H), 6.59 (d, J=7.2 Hz, 1H), 6.67-6.75 (m, 2H), 6.97 (d,J=8.4 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.64 (t, J=8.4 Hz, 1H), 8.13 (d,J=8.8 Hz, 1H), 8.74 (brs, 1H), 12.22 (brs, 1H), 12.80 (brs, 1H). MS 478(MH⁺).

Example 52a: ethyl4-amino-5-(3-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine asa brown solid (40%). MS 506 (MH⁺).

Example 53:4-amino-5-(2-(4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 53a) as a white solid. MS 424 (MH⁺).

Example 53a: ethyl4-amino-5-(2-(4-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 4-methoxybenzoic acid as a brown solid. MS 452 (MH⁺).

Example 54:4-amino-5-(2-(2-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 54a) as an off-white solid. MS 410 (MH⁺).

Example 54a: ethyl4-amino-5-(2-(2-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-hydroxybenzoic acid as a brown solid. MS 438 (MH⁺).

Example 55:4-amino-5-(2-(3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 55a) as a white solid. MS 424 (MH⁺).

Example 55a: ethyl4-amino-5-(2-(3-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-methoxybenzoic acid as a brown solid. MS 452 (MH⁺).

Example 56:4-amino-5-(2-benzamido-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-benzamido-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 56a) as a white solid. MS 394 (MH⁺).

Example 56a: ethyl4-amino-5-(2-benzamido-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and benzoic acid as a brown solid. MS 422 (MH⁺).

Example 57:4-amino-5-(2-(4-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 57a) as an off-white solid. MS 410 (MH⁺).

Example 57a: ethyl4-amino-5-(2-(4-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 4-hydroxybenzoic acid as a brown solid. MS 438 (MH⁺).

Example 58:4-amino-5-(2-(2-fluorobenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-fluorobenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 58a) as an off-white solid. MS 412 (MH⁺).

Example 58a: ethyl4-amino-5-(2-(2-fluorobenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-fluorobenzoic acid as a brown solid. MS 440 (MH⁺).

Example 59:4-amino-5-(2-(3-fluorobenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-fluorobenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 59a) as an off-white solid. MS 412 (MH⁺).

Example 59a: ethyl4-amino-5-(2-(3-fluorobenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-fluorobenzoic acid as a brown solid. MS 440 (MH⁺).

Example 60:4-amino-5-(2-(3-hydroxy-4-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-hydroxy-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 60a) as an off-white solid. MS 440 (MH⁺).

Example 60a: ethyl4-amino-5-(2-(3-hydroxy-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-hydroxy-4-methoxybenzoic acid as a brown solid. MS468 (MH⁺).

Example 61:4-amino-5-(2-(3-carbamoylbenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-carbamoylbenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 61a) as an off-white solid. MS 437 (MH⁺).

Example 61a: ethyl4-amino-5-(2-(3-carbamoylbenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-carbamoylbenzoic acid as a brown solid. MS 465(MH⁺).

Example 62:4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 62a) as a pale-yellow solid (18%). ¹H NMR (400 MHz, DMSO-d₆) δ1.49 (s, 6H), 2.76 (s, 3H), 4.25 (m, 4H), 4.48 (s, 2H), 6.87 (d, J=8.8Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.39-7.26 (m, 3H), 7.67 (t, J=7.2 Hz,1H), 7.99 (s, 1H), 8.83 (brs, 1H), 12.31 (brs, 1H), 12.71 (brs, 1H). MS452 (MH⁺).

Example 62a: ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as abrown solid (60%). MS 480 (MH⁺).

Example 63:4-amino-5-(2-(2-ethylbutanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-ethylbutanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 63a) as an off-white solid. MS 388 (MH⁺).

Example 63a: ethyl4-amino-5-(2-(2-ethylbutanamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-ethylbutanoic acid as a brown solid. MS 416 (MH⁺).

Example 64:4-amino-5-(2-(3-methoxypropanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-methoxypropanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 64a) as an off-white solid. MS 376 (MH⁺).

Example 64a: ethyl4-amino-5-(2-(3-methoxypropanamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-methoxypropanoic acid as a brown solid. MS 404(MH⁺).

Example 65:4-amino-5-(2-butyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylic

Prepared as in Example 1 from ethyl4-amino-5-(2-butyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 65a) as an off-white solid. MS 360 (MH⁺).

Example 65a: ethyl4-amino-5-(2-butyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and butyric acid as a brown solid. MS 388 (MH⁺).

Example 66:4-amino-2-methyl-5-(2-methyl-2-(tetrahydrofuran-3-carboxamido)propoxy)-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-(tetrahydrofuran-3-carboxamido)propoxy)quinoline-3-carboxylate(Example 66a) as an off-white solid. MS 388 (MH⁺).

Example 66a: ethyl4-amino-2-methyl-5-(2-methyl-2-(tetrahydrofuran-3-carboxamido)-propoxy)quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and tetrahydrofuran-3-carboxylic acid as a brown solid. MS416 (MH⁺).

Example 67:4-amino-5-(2-(4-(hydroxymethyl)benzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-(hydroxymethyl)benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 67a) as an off-white solid. MS 424 (MH⁺).

Example 67a: ethyl4-amino-5-(2-(4-(hydroxymethyl)benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 4-(hydroxymethyl)benzoic acid as a brown solid. MS 452(MH⁺).

Example 68:4-amino-5-(2-(2-methoxyacetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-methoxyacetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 68a) as an off-white solid. MS 362 (MH⁺).

Example 68a: ethyl4-amino-5-(2-(2-methoxyacetamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-methoxyacetic acid as a brown solid. MS 390 (MH⁺).

Example 69:5-(2-acetamido-2-methylpropoxy)-4-amino-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl5-(2-acetamido-2-methylpropoxy)-4-amino-2-methylquinoline-3-carboxylate(Example 69a) as an off-white solid. MS 332 (MH⁺).

Example 69a: ethyl5-(2-acetamido-2-methylpropoxy)-4-amino-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and acetic acid as a brown solid. MS 390 (MH⁺).

Example 70:4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 70a) as an off-white solid. MS 452 (MH⁺).

Example 70a: ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as abrown solid. MS 480 (MH⁺).

Example 71:4-amino-5-(2-(3,5-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3,5-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 71a) as an off-white solid. MS 454 (MH⁺).

Example 71a: ethyl4-amino-5-(2-(3,5-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3,5-dimethoxybenzoic acid as a brown solid. MS 482(MH⁺).

Example 72:4-amino-5-(2-(3,4-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3,4-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 72a) as an off-white solid. MS 454 (MH⁺).

Example 72a: ethyl4-amino-5-(2-(3,4-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3,4-dimethoxybenzoic acid as a brown solid. MS 482(MH⁺).

Example 73:4-amino-5-(2-(2-(4-methoxyphenyl)acetamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-(4-methoxyphenyl)acetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 73a) as an off-white solid. MS 438 (MH⁺).

Example 73a: ethyl4-amino-5-(2-(2-(4-methoxyphenyl)acetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-(3,4-dimethoxyphenyl)acetic acid as a brown solid.MS 466 (MH⁺).

Example 74:4-amino-5-(2-(4-fluoro-3-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-fluoro-3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 74a) as an off-white solid. MS 428 (MH⁺).

Example 74a: ethyl4-amino-5-(2-(4-fluoro-3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 4-fluoro-3-hydroxybenzoic acid as a brown solid. MS456 (MH⁺).

Example 75:4-amino-5-(2-(3-hydroxy-5-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-hydroxy-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 75a) as an off-white solid. MS 440 (MH⁺).

Example 75a: ethyl4-amino-5-(2-(3-hydroxy-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-hydroxy-5-methoxybenzoic acid as a brown solid. MS468 (MH⁺).

Example 76:4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 76a) as an off-white solid. MS 484 (MH⁺).

Example 76a: ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. etal. Bioorg. Med. Chem. Lett. 2009, 19, 4151) as a brown solid. MS 512(MH⁺).

Example 77:4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 77a) as an off-white solid. MS 484 (MH⁺).

Example 77a: ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brownsolid. MS 512 (MH⁺).

Example 78:4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 78a) as an off-white solid. MS 498 (MH⁺).

Example 78a: ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-(3-hydroxypropoxy)-4-methoxybenzoic acid as a brownsolid. MS 526 (MH⁺).

Example 79:4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 79a) as an off-white solid. MS 498 (MH⁺).

Example 79a: ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi,P. G. et al. J. Med. Chem. 1999, 42, 5131) as a brown solid. MS 526(MH⁺).

Example 80:(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)propoxy)-2-methylquinoline-3-carboxylate(Example 80a) as an off-white solid. MS 438 (MH⁺).

Example 80a: (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brownsolid. MS 466 (MH⁺).

Example 81:(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)propoxy)-2-methylquinoline-3-carboxylate(Example 81a) as an off-white solid. MS 438 (MH⁺).

Example 81a: (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brownsolid. MS 466 (MH⁺).

Example 82:(S)-4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 82a) as an off-white solid. MS 470 (MH⁺).

Example 82a: (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)pro-poxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al.Bioorg. Med. Chem. Lett. 2009, 19, 4151) as a brown solid. MS 498 (MH⁺).

Example 83:(S)-4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 83a) as an off-white solid. MS 470 (MH⁺).

Example 83a: (S)-ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)pro-poxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brown solid. MS498 (MH⁺).

Example 84:(S)-4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 84a) as an off-white solid. MS 484 (MH⁺).

Example 84a: (S)-ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)pro-poxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 3-(3-hydroxypropoxy)-4-methoxybenzoic acid as a brown solid. MS512 (MH⁺).

Example 85:(S)-4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 85a) as an off-white solid. MS 484 (MH⁺).

Example 85a: (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)pro-poxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. etal. J. Med. Chem. 1999, 42, 5131) as a brown solid. MS 512 (MH⁺).

Example 86:(R)-4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methylquinoline-3-carboxylicacid (SID 47687595)

Prepared as in Example 1 from (R)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)-propoxy)-2-methylquinoline-3-carboxylate(Example 86a) as a white solid (43%). ¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.10 (m, 5H), 1.34-1.31 (m, 2H), 1.69-1.62 (m, 5H), 2.11-2.05 (m,1H), 2.69 (s, 3H), 3.93 (t, J=9.2 Hz, 1H), 4.13 (dd, J=4, 9.6 Hz, 1H),4.14-4.11 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.49(t, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H). MS 386 (MH⁺).

Example 86a: (R)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example86b) and cyclohexanecarboxylic acid as brown solid (31%). MS 414 (MH⁺).

Example 86b: (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (R)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)-carbamate (Example 86c) andethyl 3-oxobutanoate as brown solid. MS 304 (MH⁺).

Example 86c: (R)-benzyl (1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate

Prepared as in Example 24c from(R)-2-amino-6-(2-aminopropoxy)benzonitrile (Example 86d) as brown solid(79%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (d, J=6.4 Hz, 3H), 3.81 (d,J=8.4 Hz, 1H), 3.95-3.92 (m, 1H), 4.99 (s, 2H), 5.36 (s, 2H), 5.96 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.13 (t, J=8.4 Hz,1H), 7.44-7.38 (m, 5H). MS 326 (MH⁺).

Example 86d: (R)-2-amino-6-(2-aminopropoxy)benzonitrile

Prepared as in Example 24d from (R)-2-aminopropan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (81%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H),5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t,J=8.3 Hz, 1H). MS 192 (MH⁺).

Example 87:(R)-4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (R)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate(Example 87a) as an off-white solid (32%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31 (d, J=6.8 Hz, 3H), 2.66 (s, 3H), 4.14 (t, J=9.2 Hz, 1H), 4.28 (dd,J=3.6, 9.6 Hz, 1H), 4.70-4.55 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.26 (d,J=8.4 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.75 (dd, J=1.2, 6.0 Hz, 2H),8.71 (dd, J=1.2, 6.0 Hz, 2H), 8.95 (d, J=8.0 Hz, 1H). MS 409 (MH⁺).

Example 87a: (R)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example86b) and isonicotinic acid as brown solid (41%). MS 409 (MH⁺).

Example 88:(R)-4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (R)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 88a) as a white solid (51%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.28(d, J=7.2 Hz, 3H), 2.65 (s, 3H), 4.11 (t, J=8.8 Hz, 1H), 4.22 (dd,J=4.0, 10 Hz, 1H), 4.65-4.55 (m, 1H), 6.88 (d, J=8.0, 2H), 7.25-7.13 (m,4H), 7.48 (t, J=8.0 Hz, 1H), 8.49 (d, J=8.0, 1H), 9.93 (brs, 1H). MS 396(MH⁺).

Example 88a: (R)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example86b) and 3-hydroxybenzoic acid as brown solid (36%). MS 424 (MH⁺).

Example 89:(S)-4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methyl-quinoline-3-carboxylicacid (SID 47039333)

Prepared as in Example 1 from (S)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 89a) as an off-white solid (31%). ¹H NMR (400 MHz, DMSO-d₆) δ1.34-1.11 (m, 5H), 1.72-1.51 (m, 5H), 2.08-1.79 (m, 5H), 2.44-2.35 (m1H), 2.52 (s, 3H), 3.55-3.45 (m, 2H), 4.02 (dd, J=6.8, 9.2 Hz, 1H), 4.17(dd, J=4.8, 10.0 Hz, 1H), 4.45-4.38 (m, 1H), 6.75 (d, J=7.2 Hz), 7.11(d, J=7.6 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H). MS 412 (MH⁺).

Example 89a: (S)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 89b) and cyclohexanecarboxylic acid as brown solid (46%). MS440 (MH⁺).

Example 89b: (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example89c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH⁺).

Example 89c: (S)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 24c from(S)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile (Example 89d) asbrown solid (79%). MS 351 (MH⁺).

Example 89d: (S)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile

Prepared as in Example 24d from (S)-pyrrolidin-2-ylmethanol and2-amino-6-fluoro-benzonitrile as brown solid (51%). MS 218 (MH⁺).

Example 90:(S)-4-amino-5-((1-isobutyrylpyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methylquinoline-3-carboxylate(Example 90a) as an off-white solid (39%). ¹H NMR (400 MHz, DMSO-d₆) δ0.99 (dd, J=2.0, 6.8 Hz, 6H), 2.05-1.83 (m, 4H), 2.65 (s, 3H), 3.53 (t,J=7.2 Hz, 2H), 4.08 (dd, J=6.8, 10.0 Hz, 1H), 4.20 (dd, J=6.0, 10.0 Hz,1H), 4.54 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.50(t, J=8.0 Hz, 1H). MS 344 (MH⁺).

Example 90a: (S)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 89b) and isobutyric acid as brown solid (46%). MS 400 (MH⁺).

Example 91:(S)-5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylate(Example 91a) as an off-white solid (23%). ¹H NMR (400 MHz, DMSO-d₆) δ1.98 (s, 3H), 2.03-1.82 (m, 4H), 2.71 (s, 3H), 3.48 (t, J=6.0 Hz, 2H),4.05 (dd, J=6.4, 10.0 Hz, 1H), 4.22 (dd, J=6.8, 10.0 Hz, 1H), 4.54-4.46(m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.54 (t, J=10.0Hz, 1H). MS 344 (MH⁺).

Example 91a: (S)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 89b) and acetic anhydride as brown solid (31%). MS 372 (MH⁺).

Example 92:(R)-4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from (R)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 92a) as an off-white solid (37%). ¹H NMR (400 MHz, DMSO-d₆) δ1.34-1.11 (m, 5H), 1.72-1.51 (m, 5H), 2.08-1.79 (m, 5H), 2.44-2.35 (m1H), 2.52 (s, 3H), 3.55-3.45 (m, 2H), 4.02 (dd, J=6.8, 9.2 Hz, 1H), 4.17(dd, J=4.8, 10.0 Hz, 1H), 4.45-4.38 (m, 1H), 6.75 (d, J=7.2 Hz), 7.11(d, J=7.6 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H). MS 412 (MH⁺).

Example 92a: (R)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 92b) and cyclohexanecarboxylic acid as brown solid (39%). MS440 (MH⁺).

Example 92b: (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from (R)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example92c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH⁺).

Example 92c: (R)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 24c from(R)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile (Example 92d) asbrown solid (71%). MS 351 (MH⁺).

Example 92d: (R)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile

Prepared as in Example 24d from (R)-pyrrolidin-2-ylmethanol and2-amino-6-fluoro-benzonitrile as brown solid (57%). MS 218 (MH⁺).

Example 93:(R)-4-amino-5-((1-isobutyrylpyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (R)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methylquinoline-3-carboxylate(Example 93a) as an off-white solid (44%). ¹H NMR (400 MHz, DMSO-d₆) δ0.99 (dd, J=2.0, 6.8 Hz, 6H), 2.05-1.83 (m, 4H), 2.65 (s, 3H), 3.53 (t,J=7.2 Hz, 2H), 4.08 (dd, J=6.8, 10.0 Hz, 1H), 4.20 (dd, J=6.0, 10.0 Hz,1H), 4.54 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.50(t, J=8.0 Hz, 1H). MS 344 (MH⁺).

Example 93a: (R)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate(Example 92b) and isobutyric acid as brown solid (39%). MS 400 (MH⁺).

Example 94:(R)-5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (R)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylate(Example 94a) as an off-white solid (19%). ¹H NMR (400 MHz, DMSO-d₆) δ1.98 (s, 3H), 2.03-1.82 (m, 4H), 2.71 (s, 3H), 3.48 (t, J=6.0 Hz, 2H),4.05 (dd, J=6.4, 10.0 Hz, 1H), 4.22 (dd, J=6.8, 10.0 Hz, 1H), 4.54-4.46(m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.54 (t, J=10.0Hz, 1H). MS 344 (MH⁺).

Example 94a: (R)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate(Example 92b) and acetic anhydride as brown solid (28%). MS 372 (MH⁺).

Example 95:(S)-4-amino-5-(2-(2-hydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95a) as a white solid (82%). MS 424 (MH⁺).

Example 95a: (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)-3-methylbutoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 2-hydroxybenzoic acid as brown solid (56%). MS 452(MH⁺).

Example 95b: (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl1-(3-amino-2-cyanophenoxy)-3-methylbutan-2-ylcarbamate (Example 95c) andethyl 3-oxobutanoate as brown solid (79%). MS 332 (MH⁺).

Example 95c: (S)-benzyl1-(3-amino-2-cyanophenoxy)-3-methylbutan-2-ylcarbamate

Prepared as in Example 24c from(S)-2-amino-6-(2-amino-3-methylbutoxy)benzonitrile (Example 95d) asbrown solid (82%). MS 354 (MH⁺).

Example 95d: (S)-2-amino-6-(2-amino-3-methylbutoxy)benzonitrile

Prepared as in Example 24d from (S)-2-amino-3-methylbutan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (71%). MS 220 (MH⁺).

Example 96:(S)-4-amino-5-(2-(3-hydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 96a) as a white solid (83%). MS 424 (MH⁺).

Example 96a: (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)-3-methylbutoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 3-hydroxybenzoic acid as brown solid (35%). MS 452(MH⁺).

Example 97:(S)-4-amino-5-(2-(2-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 97a) as an off-white solid (78%). MS 410 (MH⁺).

Example 97a: (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 2-hydroxybenzoic acid as brown solid (46%). MS 438 (MH⁺).

Example 97b: (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl1-(3-amino-2-cyanophenoxy)butan-2-ylcarbamate (Example 97c) and ethyl3-oxobutanoate as brown solid (75%). MS 318 (MH⁺).

Example 97c: (S)-benzyl 1-(3-amino-2-cyanophenoxy)butan-2-ylcarbamate

Prepared as in Example 24c from(S)-2-amino-6-(2-aminobutoxy)benzonitrile (Example 97d) as brown solid(87%). MS 340 (MH⁺).

Example 97d: (S)-2-amino-6-(2-aminobutoxy)benzonitrile

Prepared as in Example 24d from (S)-2-aminobutan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (73%). MS 206 (MH⁺).

Example 98:(S)-4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxy-benzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 98a) as an off-white solid (83%). MS 484 (MH⁺).

Example 98a: (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)-butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg.Med. Chem. Lett. 2009, 19, 4151) as brown solid (38%). MS 512 (MH⁺).

Example 99:(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)butoxy)-2-methylquinoline-3-carboxylate(Example 99a) as an off-white solid (78%). MS 452 (MH⁺).

Example 99a: (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid(40%). MS 480 (MH⁺).

Example 100:(S)-4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 100a) as an off-white solid (79%). MS 498 (MH⁺).

Example 100a: (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J.Med. Chem. 1999, 42, 5131) as brown solid (41%). MS 526 (MH⁺).

Example 101:(S)-4-amino-5-(2-(3,5-dihydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 101a) as an off-white solid (69%). MS 426 (MH⁺).

Example 101a: (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)butoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 3,5-dihydroxybenzoic acid as brown solid (37%). MS 454 (MH⁺).

Example 102:(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)butoxy)-2-methylquinoline-3-carboxylate(Example 102a) as an off-white solid (71%). MS 452 (MH⁺).

Example 102a: (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid(46%). MS 480 (MH⁺).

Example 103:(S)-4-amino-5-(2-(3-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 103a) as an off-white solid (72%). MS 410 (MH⁺).

Example 103a: (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b)and 3-hydroxybenzoic acid as brown solid (49%). MS 438 (MH⁺).

Example 104:(S)-4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 104a) as an off-white solid (69%). MS 512 (MH⁺).

Example 104a: (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi,P. G. et al. J. Med. Chem. 1999, 42, 5131) as brown solid (29%). MS 540(MH⁺).

Example 105:(S)-4-amino-5-(2-(3,5-dihydroxybenzamido)-3-methylbutoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 105a) as a white solid (72%). MS 440 (MH⁺).

Example 105a: (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 3,5-dhydroxybenzoic acid as brown solid (29%). MS 468(MH⁺).

Example 106:(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 106a) as a white solid (81%). MS 466 (MH⁺).

Example 106a: (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid asbrown solid (36%). MS 494 (MH⁺).

Example 107:(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 107a) as an off-white solid (76%). MS 466 (MH⁺).

Example 107a: (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid asbrown solid (29%). MS 494 (MH⁺).

Example 108:4-amino-5-((4-(isonicotinamido)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((4-(isonicotinamido)cyclohexyl)-methoxy)-2-methylquinoline-3-carboxylate(Example 108a) as an off-white solid (43%). ¹H NMR (400 MHz, DMSO-d₆) δ1.52-2.01 (m, 8H), 2.13 (m, 1H), 2.74 (s, 3H), 3.99 (m, 1H), 4.18 (d,J=6.8 Hz, 2H), 7.05 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.66 (t,J=8.4 Hz, 1H), 7.71 (d, J=6.0 Hz, 2H), 8.40 (d, J=6.8 Hz, 1H), 8.71 (d,J=6.0 Hz, 2H), 12.70 (brs, 1H). MS 435 (MH⁺).

Example 108a: ethyl4-amino-5-((4-(isonicotinamido)cyclohexyl)-methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 2a fromN-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)-isonicotinamide(Example 108b) and ethyl 3-oxobutanoate as a yellow solid (25%). MS 463(MH⁺).

Example 108b:N-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)isonicotinamide

Prepared as in Example 22b fromN-(4-(Hydroxymethyl)cyclohexyl)isonicotinamide (Example 108c) and2-amino-6-fluorobenzonitrile as a colorless oil (6%). MS 351 (MH⁺).

Example 108c: N-(4-(Hydroxymethyl)cyclohexyl)isonicotinamide

Prepared as in Example 24a from (4-Aminocyclohexyl)methanol andisonicotinic acid as a yellow oil (100%). MS 235 (MH⁺).

Example 109:4-amino-5-((2-methoxycyclohexyl)oxy)-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-5-((2-methoxycyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 109a) as a white solid (79%). ¹H NMR (400 MHz, DMSO-d₆) δ1.20-1.68 (m, 6H), 2.16 (m, 2H), 2.78 (s, 3H), 3.34 (s, 3H), 3.58 (m,1H), 4.50 (m, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.67(t, J=8.8 Hz, 1H), 8.92 (brs, 1H), 12.14 (brs, 1H), 12.86 (brs, 1H). MS331 (MH⁺).

Example 109a: ethyl4-amino-5-((2-methoxycyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-Amino-6-(2-methoxycyclohexyloxy)benzonitrile (Example 109b) and ethyl3-oxobutanoate as a pale yellow oil (16%). MS 359 (MH⁺).

Example 109b: 2-Amino-6-(2-methoxycyclohexyloxy)benzonitrile

Prepared as in Example 22b from 2-methoxycyclohexanol and2-amino-6-fluoro-benzonitrile as a yellow oil (34%). MS 247 (MH⁺).

Example 110:4-amino-5-((1-(3-hydroxybenzoyl)piperidin-3-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-3-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 110a) as a white solid (35%). MS 436 (MH⁺).

Example 110a: ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-3-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-2-methyl-5-(piperidin-3-ylmethoxy)-quinoline-3-carboxylate(Example 110b) and 3-hydroxybenzoic acid as a white solid (34%). MS 464(MH⁺).

Example 110b: ethyl4-amino-2-methyl-5-(piperidin-3-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from benzyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example110c) and ethyl 3-oxobutanoate as a yellow oil (21%). MS 344 (MH⁺).

Example 110c: benzyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 24c from2-amino-6-(piperidin-3-ylmethoxy)benzonitrile (Example 110d) as a yellowsolid (70%).

Example 110d: 2-amino-6-(piperidin-3-ylmethoxy)benzonitrile

Prepared as in Example 24d from 3-piperidinemethanol and2-amino-6-fluoro-benzonitrile as a light yellow solid (27%). MS 232(MH⁺).

Example 111:4-amino-5-((1-(3-hydroxybenzoyl)piperidin-2-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 111a) as an off-white solid (35%). ¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.89 (m, 6H), 2.74 (s, 3H), 3.44 (m, 2H), 4.27 (m, 1H), 4.75 (m,2H), 5.29 (m, 1H), 6.64-6.73 (m, 2H), 6.78 (d, J=7.2 Hz, 1H), 7.18 (m,2H), 7.26 (d, J=8.4 Hz, 1H), 7.68 (m, 1H), 8.87 (brs, 1H), 9.73 (brs,1H), 11.96 (brs, 1H), 12.70 (brs, 1H). MS 436 (MH⁺).

Example 111a: ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-2-methyl-5-(piperidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 111b) and 3-hydroxybenzoic acid as a white solid (28%). MS 464(MH⁺).

Example 111b: ethyl4-amino-2-methyl-5-(piperidin-2-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from benzyl2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example111c) and ethyl 3-oxobutanoate as a colorless oil (13%). MS 344 (MH⁺).

Example 111c: benzyl2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 24c from2-amino-6-(piperidin-2-ylmethoxy)benzonitrile (Example 111d) as a yellowsolid (100%). MS 366 (MH⁺).

Example 111d: 2-Amino-6-(piperidin-2-ylmethoxy)benzonitrile

Prepared as in Example 24d from 2-piperidinemethanol and2-amino-6-fluoro-benzonitrile as a light yellow solid (64%). MS 232(MH⁺).

Example 112: 4-amino-5-cyclopropyl-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-5-cyclopropyl-2-methylquinoline-3-carboxylate (Example 112a) asa white solid (85%). ¹H NMR (400 MHz, MeOH-d4) δ 1.03 (m, 2H), 1.31 (m,2H), 2.53 (m, 1H), 2.81 (s, 3H), 7.50 (m, 1H), 7.58 (m, 1H), 7.73 (m,1H). MS 243 (MH⁺).

Example 112a: ethyl4-amino-5-cyclopropyl-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-cyclopropylbenzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as a pale yellow solid (80%). MS 271 (MH⁺).

Example 113:4-amino-2-(carboxymethyl)-5-(2-cyclohexylethyl)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-cyclohexylethyl)-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate(Example 113a) as an orange solid (69%). ¹H NMR (400 MHz, DMSO-d₆) δ0.89-0.92 (m, 2H), 1.14-1.29 (m, 4H), 1.44-1.49 (m, 2H), 1.56-1.66 (m,4H), 1.73-1.76 (m, 1H), 3.15 (t, J=8.0 Hz, 2H), 3.70 (s, 2H), 7.09-7.11(m, 1H), 7.38-7.42 (m, 1H), 7.46-7.51 (m, 2H). MS 338 (MH⁺—H₂O).

Example 113a: ethyl4-amino-5-(2-cyclohexylethyl)-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(2-cyclohexylethyl)benzonitrile(Example 113b) and diethyl 3-oxopentanedioate as an orange solid (33%).¹H NMR (400 MHz, DMSO-d₆) δ 0.87-0.96 (m, 2H), 1.14-1.22 (m, 7H),1.27-1.32 (m, 4H), 1.47-1.52 (m, 2H), 1.61-1.68 (m, 4H), 1.74-1.77 (m,2H), 3.21-3.25 (m, 2H), 4.03 (s, 2H), 4.09 (q, J=8.0 Hz, 2H), 4.27 (q,J=8.0 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.63(brs, 2H). MS 413 (MH⁺).

Example 113b: 2-amino-6-(2-cyclohexylethyl)benzonitrile

Prepared as in Example 21b from2-amino-6-(cyclohexylethynyl)benzonitrile (Example 113c) as an orangesolid (36%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.90-0.95 (m, 2H), 1.16-1.24(m, 4H), 1.41-1.46 (m, 2H), 1.60-1.75 (m, 5H), 2.58-2.62 (m, 2H), 5.90(s, 2H), 6.48 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 7.18 (t, J=4.0Hz, 1H). MS 229 (MH⁺).

Example 113c: 2-amino-6-(cyclohexylethynyl)benzonitrile

Prepared as in Example 21c from ethynylcyclohexane and2-amino-6-bromobenzonitrile as a brown oil (100%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.24-1.77 (m, 10H), 2.70 (m, 1H), 6.13 (s, 2H), 6.64 (d,J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H). MS 225(MH⁺).

Example 114: 4-amino-5-(3-methoxyphenyl)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-methoxyphenyl)-2-methylquinoline-3-carboxylate (Example114a) as an off-white solid (38%). MS 309 (MH⁺).

Example 114a: ethyl4-amino-5-(3-methoxyphenyl)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile (Example 114b) andethyl 3-oxobutanoate as a pale yellow solid (55%). MS 337 (MH⁺).

Example 114b: 3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile

To a stirred solution of 2-amino-6-bromobenzonitrile (195 mg, 1.0 mmol)and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) wasadded aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reactionsolution was degassed by bubbling N₂ for 2 minutes.

Palladium tetrakistriphenylphosphine (5% mol) was added to the reactionmixture and the reaction vessel was placed in a microwave reactor andirradiated at 165° C. for 20 minutes. The precipitate was removed byfiltration and the filtrate concentrated. The residue was purified byHPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the titlecompound as an off-white solid (180 mg, 80%). MS 225 (MH⁺).

Example 115:4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylate (Example115a) as a white solid (84%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.03-1.29 (m,5H), 1.63-1.82 (m, 5H), 1.94 (m, 1H), 2.75 (s, 3H), 4.06 (d, J=6.4 Hz,2H), 7.03 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.4 Hz,1H). MS 315 (MH⁺).

Example 115a: ethyl4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cyclohexylmethoxy)benzonitrile(Example 115b) and ethyl 3-oxobutanoate as a pale yellow solid (47%). ¹HNMR (400 MHz, MeOD) δ 1.12-1.37 (m, 6H), 1.42 (t, J=4.0 Hz, 3H),1.73-2.01 (m, 5H), 2.68 (s, 3H), 4.06 (d, J=4.0 Hz, 2H), 4.42 (q, J=8.0Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0Hz, 1H). MS 343 (MH⁺).

Example 115b: 2-amino-6-(cyclohexylmethoxy)benzonitrile

Prepared as in Example 22b from cyclohexylmethanol and2-amino-6-fluorobenzonitrile as a colorless oil (50%). ¹H NMR (400 MHz,CDCl₃) δ 1.07-1.09 (m, 2H), 1.28-1.32 (m, 3H), 1.75-1.90 (m, 6H), 3.79(d, J=6.4 Hz, 2H), 4.37 (s, 2H), 6.20 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.4Hz, 1H), 7.19 (t, J=8.4 Hz, 1H). MS 231 (MH⁺).

Example 116:4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylic Acid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-phenoxyquinoline-3-carboxylate (Example 116a) as anoff-white solid (47%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.77 (s, 3H), 6.60(d, J=4.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.40(dd, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.60 (t, J=8.0 Hz, 1H), 8.81(brs, 1H), 12.20 (brs, 1H), 12.81 (brs, 1H). MS 295 (MH⁺).

Example 116a: ethyl 4-amino-2-methyl-5-phenoxyquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-phenoxybenzonitrile and ethyl3-oxobutanoate as a yellow oil (72%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.32(t, J=8.0 Hz, 3H), 2.59 (s, 3H), 4.33 (q, J=8.0 Hz, 2H), 6.61 (dd, J=8.0Hz, 1H), 7.16 (d, J=4.0 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.39-7.52 (m,4H), 7.93 (brs, 2H). MS 323 (MH⁺).

Example 117:4-amino-5-(3-((4-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-((4-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 117a) as an off-white solid (38%). MS 438 (MH⁺).

Example 117a: ethyl4-amino-5-(3-((4-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and (4-methoxyphenyl)methanamine as a yellow solid(100%). MS 466 (MH⁺).

Example 118:4-amino-2-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-3-carboxylate(Example 118a) as an off-white solid (80%). ¹H NMR (400 MHz, DMSO-d₆) δ1.81 (m, 2H), 2.06 (m, 2H), 2.75 (s, 3H), 3.87 (m, 2H), 4.91 (m, 1H),7.15 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H).MS 303 (MH⁺).

Example 118a: ethyl4-amino-2-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (Example 118b) andethyl 3-oxobutanoate as a pale yellow solid (51%). MS 331 (MH⁺).

Example 118b: 2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile

Prepared as in Example 22b from tetrahydro-2H-pyran-4-ol and2-amino-6-fluorobenzonitrile as a colorless oil (48%). ¹H NMR (400 MHz,CDCl₃) δ 1.87 (m, 2H), 2.00 (m, 2H), 3.63 (m, 2H), 4.00 (m, 2H), 4.42(s, 2H), 4.58 (m, 1H), 6.23 (d, J=8.4 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H),7.20 (t, J=8.4 Hz, 1H). MS 219 (MH⁺).

Example 119:4-amino-5-(2,2-dimethyl-3-oxo-3-((pyridin-4-ylmethyl)amino)propoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-((pyridin-4-ylmethyl)amino)propoxy)-2-methylquinoline-3-carboxylate(Example 119a) as an off-white solid (44%). MS 409 (MH⁺).

Example 119a: ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-((pyridin-4-ylmethyl)amino)pro-poxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and pyridin-4-ylmethanamine as a brown solid (43%).MS 437 (MH⁺).

Example 120:4-amino-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methylquinoline-3-carboxylate(Example 120a) as an off-white solid (33%). ¹H NMR (400 MHz, DMSO-d₆) δ0.98 (s, 6H), 2.75 (s, 3H), 3.37 (s, 2H), 3.97 (s, 2H), 5.12 (brs, 1H),7.01 (d, J=8.4 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H),9.27 (brs, 1H), 12.23 (brs, 1H), 12.73 (brs, 1H). MS 305 (MH⁺).

Example 120a: ethyl4-amino-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Tachdjian, C. etal. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as apale yellow solid (26%). MS 333 (MH⁺).

Example 121:4-amino-5-((1-isobutyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-isobutyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 121a) as a white solid (38%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.99(m, 6H), 1.13-1.23 (m, 2H), 1.78-1.89 (m, 2H), 2.26 (brs, 1H), 2.51 (m,1H), 2.78 (brs, 3H), 2.88 (m, 1H), 3.06 (t, J=12.0 Hz, 1H), 4.02 (d,J=12.0 Hz, 1H), 4.41 (m, 2H), 4.44 (d, J=12.0 Hz, 1H), 7.07 (brs, 1H),7.28 (d, J=8.0 Hz, 1H), 7.70 (brs, 1H), 8.76 (brs, 1H), 12.37 (brs, 1H),12.67 (brs, 1H). MS 386 (MH⁺).

Example 121a: ethyl4-amino-5-((1-isobutyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile(Example 121b) and ethyl 3-oxobutanoate as a yellow oil (36%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.97 (m, 6H), 1.32 (t, J=8.0 Hz, 3H), 1.79-1.88 (m,3H), 2.15-2.18 (m, 2H), 2.55 (s, 3H), 2.86 (m, 1H), 3.04 (m, 1H), 4.00(m, 2H), 4.07 (d, J=4.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 4.46 (m, 1H),6.91 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H),8.07 (brs, 2H). MS 414 (MH⁺).

Example 121b:2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 22b from1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one (Example 121c)and 2-amino-6-fluorobenzonitrile as a pale yellow solid (21%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.99 (m, 6H), 1.13-1.24 (m, 2H), 1.74-1.81 (m, 2H),1.99 (m, 1H), 2.55 (m, 1H), 2.84 (m, 1H), 3.01 (m, 1H), 3.88 (m, 2H),4.02 (m, 1H), 4.46 (m, 1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34(d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H). MS 302 (MH⁺).

Example 121c: 1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one

Prepared as in Example 24a from isobutyric acid andpiperidin-4-ylmethanol as a colorless oil (36%). MS 186 (MH⁺).

Example 122:4-amino-5-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 122a) as a white solid (64%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.70(d, J=6.8 Hz, 3H), 0.89 (t, J=7.6 Hz, 6H), 0.9-1.0 (m, 2H), 1.04 (m,2H), 1.50-1.82 (m, 5H), 1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.72 (s,3H), 4.52 (t-d, J=10.4, 4.4 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.21 (d,J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 8.68 (brs, 1H), 11.72 (brs, 1H),12.73 (brs, 1H). MS 357 (MH⁺).

Example 122a: ethyl4-amino-5-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclo-hexyl)oxy)benzonitrile(Example 122b) and ethyl 3-oxobutanoate as a pale yellow solid (43%). MS385 (MH⁺).

Example 122b:2-amino-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)benzonitrile

Prepared as in Example 22b from(1R,2S,5R)-2-isopropyl-5-methylcyclohexanol and2-amino-6-fluorobenzonitrile as a white solid (51%). MS 273 (MH⁺).

Example 123:4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid hydrochloride

To a stirred suspension of4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid (Example 38, 263 mg, 0.544 mmol) in EtOH (2 mL) was added HCl inEtOH (1.25 N, 479 uL, 1.1 equiv.). The mixture was stirred at roomtemperature until it became a clear solution (0.5 h). The solution wasconcentrated under reduced pressure to give the title compound as awhite solid, which was further purified by re-crystallization fromEtOH/H₂O and dried under vacuum overnight (248 mg, 87%). ¹H NMR (400MHz, DMSO-d₆) δ 1.51 (s, 6H), 2.80 (s, 3H), 3.68 (t, J=5.2 Hz, 2H), 3.74(s, 3H), 3.97 (t, J=5.2 Hz, 1H), 4.53 (s, 2H), 6.59 (s, 1H), 6.92 (s,1H), 6.94 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.86(t, J=8.4 Hz, 1H), 8.03 (s, 1H), 9.40 (s, 1H), 9.98 (s, 1H). 484(MH⁺—HCl).

Example 124:4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylic acidHydrochloride

Prepared as in Example 123 from4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylic acid(Example 18) as a white solid (100%). ¹H NMR (400 MHz, DMSO-d₆) δ1.29-1.37 (m, 2H), 1.51-1.66 (m, 4H), 1.82-1.90 (m, 2H), 2.43-2.51 (m,1H), 2.81 (s, 3H), 4.18 (d, J=7.2 Hz, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.60(d, J=8.4 Hz, 1H), 7.84 (t, J=8.4 Hz, 1H), 9.25 (brs, 1H), 9.86 (brs,1H). MS 301 (MH⁺—HCl).

Example 125:4-amino-5-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 125a) as a white solid (23%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.67(brs, 2H), 2.09 (m, 2H), 2.31 (brs, 1H), 2.92 (brs, 2H), 3.48 (brs, 2H),3.82 (s, 3H), 4.15 (brs, 2H), 4.25 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz,2H), 7.14 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz,2H), 7.76 (t, J=8.0 Hz, 1H). MS 436 (MH⁺).

Example 125a: ethyl4-amino-5-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile(Example 125b) and ethyl 3-oxobutanoate as an off-white solid (30%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.29-1.33 (m, 5H), 1.74 (m, 2H), 1.92 (m, 3H),2.54 (s, 3H), 2.83 (m, 2H), 3.38 (s, 2H), 3.71 (s, 3H), 4.04 (d, J=8.0Hz, 2H), 4.31 (q, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 8.04 (brs, 2H). MS 464 (MH⁺).

Example 125b:2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 22b from(1-(4-methoxybenzyl)piperidin-4-yl)methanol (Example 125c) and2-amino-6-fluorobenzonitrile as an orange solid (19%). MS 352 (MH⁺).

Example 125c: (1-(4-methoxybenzyl)piperidin-4-yl)methanol

To a solution of 4-piperidinemethanol (2.28 g, 19.78 mmol) and4-methoxybenzaldehyde (2.30 mL, 19.77 mmol) in THF/DCE (1:1 by volume,100 mL) was added acetic acid (1 mL), followed by NaBH(OAc)₃ (16.76 g,79.08 mmol) in small portions. The reaction mixture was stirred at roomtemperature overnight under N₂. The reaction was diluted with DCM andbasified to pH=10 with 2 N NaOH solution. The organic layer wasseparated, dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica gel(Eluent: 60% EtOAc in hexanes) to give the title compound as a paleyellow oil (2.13 g, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.04-1.13 (m, 2H),1.28-1.32 (m, 1H), 1.58-1.61 (m, 2H), 1.79-1.86 (m, 2H), 2.75-2.77 (m,2H), 3.22 (t, J=8.0 Hz, 2H), 3.34 (s, 2H), 3.72 (s, 3H), 4.38 (t, J=4.0Hz, 1H), 6.85 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H). MS 236 (MH⁺).

Example 126:4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)-methoxy)-2-methylquinoline-3-carboxylate(Example 126a) as a yellow solid (76%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.00(d, J=6.8 Hz, 6H), 1.15-2.32 (m, 10H), 2.75 (s, 3H), 3.82 (o, J=7.6 Hz,1H), 4.16 (d, J=6.8 Hz, 2H), 7.07 (br d, J=7.2 Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.67 (br t, 1H), 8.77 (s, 1H), 12.23(s, 1H), 12.66 (s, 1H). MS 400 (MH⁺).

Example 126a: ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from4-((3-amino-2-cyanophenoxy)methyl)-N-isopropylcyclohexanecarboxamide(Example 126b) and ethyl 3-oxobutanoate as a pale yellow solid (37%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H),1.38-1.81 (m, 8H), 1.88 (m, 1H), 2.25 (m, 1H), 2.55 (s, 3H), 3.82 (bro,J=7.6 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 4.31 (q, J=7.6 Hz, 2H), 6.93 (d,J=7.6 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.50 (m, 2H), 8.09 (s, 2H). MS428 (MH⁺).

Example 126b:4-((3-amino-2-cyanophenoxy)methyl)-N-isopropylcyclohexanecarboxamide

Prepared as in Example 21b from4-((2-cyano-3-nitrophenoxy)methyl)-N-isoproplycyclo-hexanecarboxamide(Example 126c) as a yellow solid (81%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.99(d, J=5.6 Hz, 6H), 1.22-1.99 (m, 9H), 2.17 (m, 1H), 3.80 (m, 1H), 3.88(d, J=7.2 Hz, 2H), 5.94 (brs, 2H), 6.18 (t, J=8.0 Hz, 1H), 6.23 (d,J=8.0 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 7.44 (s, 1H). MS 316 (H+).

Example 126c:4-((2-cyano-3-nitrophenoxy)methyl-N-isopropylcyclohexancarboxamide

To a solution of 4-(hydroxymethyl)-N-isopropylcyclohexanecarboxamide(Example 126d, 480 mg, 2.41 mmol) in dry THF (10 mL) was added NaH (60%in mineral oil, 116 mg, 4.82 mmol) in small portions at 0° C. under N₂.The reaction mixture was stirred at 0° C. under N₂ for 2 h. To thissolution was added 2,6-dinitrobenzonitrile (465 mg, 2.41 mmol), and thereaction mixture was stirred at 0° C.-RT for another 2 h, and then at60° C. overnight under N₂ and cooled down to room temperature. Thereaction was quenched with brine, and extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified by chromatography on silica gel (eluent: 50% EtOAc in hexanes)to give the title compound as yellow solid (594 mg, 71%). ¹H NMR (400MHz, DMSO-d₆) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.19 (m, 1H),3.79 (m, 1H), 4.15 (d, J=7.6 Hz, 2H), 7.45 (brs, 1H), 7.78 (d, J=7.2 Hz,1H), 7.88 (m, 2H). MS 346 (H+).

Example 126d: 4-(hydroxymethyl)-N-isopropylcyclohexanecarboxamide

Prepared as in Example 24a from 4-(hydroxymethyl)cyclohexanecarboxylicacid and propan-2-amine as a colorless oil (57%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.12 (m, 1H), 3.28(t, J=7.6 Hz, 2H), 3.79 (m, 1H), 4.34 (s, 1H), 7.43 (s, 1H). MS 200(MH⁺).

Example 127: 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylicacid Hydrochloride

To a suspension of4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example36, 1.0 g, 3.33 mmol) in ethanol (10 mL) was added 1.25 M solution ofHCl in ethanol (2.93 mL, 3.66 mmol). The clear solution was stirred for30 minutes and evaporated to dryness to provide4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acidhydrochloride (1.12 g, 100%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.30 (m, 1H), 1.39-1.47 (m, 2H), 1.53-1.72 (m, 5H), 2.01-2.05 (m, 2H),2.82 (s, 3H), 4.78-4.82 (m, 1H), 7.29-7.31 (d, J=8.0 Hz, 1H), 7.61-7.63(d, J=8.0 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 9.30 (bs, 1H), 9.93 (bs, 1H).MS 301 (MH⁺—HCl).

Example 128: sodium4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate

To a solution of4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example36, 1.0 g, 3.33 mmol) in ethanol (20 mL) was added a solution of NaHCO₃(294 mg, 3.50 mmol) in water (15 mL). The mixture was stirred and warmedup to 60° C. until the solution become clear then evaporated to drynessto provide sodium4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (1.07 g, 100%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.25-1.45 (m, 3H),1.50-1.70 (m, 5H), 1.53-1.72 (m, 5H), 1.98-2.00 (m, 2H), 2.64 (s, 3H),4.59-4.63 (m, 1H), 6.87-6.89 (d, J=7.6 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz,1H), 7.42 (t, J=8.0 Hz, 1H). MS 301 (MH⁺+H-Na).

Example 129:(±)-4-amino-5-((2-(5-(isopropylcarbamoyl)-2-methoxyphenoxy)cyclohexyl)-oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from (±)-ethyl4-amino-5-((2-(5-(isopropylcarbamoyl)-2-methoxyphenoxy)cyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 129a) as a white solid (34%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.15(d, J=8.0 Hz, 6H), 1.35-1.51 (m, 3H), 1.63-1.73 (m, 3H), 2.09 (d, J=12.0Hz, 1H), 2.24 (d, J=12.0 Hz, 1H), 2.72 (s, 3H), 3.56 (s, 3H), 3.99-4.07(m, 1H), 4.71-4.78 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 7.24 (d, J=12.0 Hz,2H), 7.42 (dd, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.66 (t, J=8.0 Hz,1H), 8.03 (d, J=8.0 Hz, 1H), 8.64 (brs, 1H), 12.00 (brs, 1H), 12.61(brs, 1H). MS 508 (MH⁺).

Example 129a: (±)-ethyl4-amino-5-((2-(5-(isopropylcarbamoyl)-2-methoxyphenoxy)-cyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from(±)-3-((2-(3-amino-2-cyanophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide(Example 129b) and ethyl 3-oxobutanoate as a yellow solid (78%). MS 536(MH⁺).

Example 129b:(±)-3-((2-(3-amino-2-cyanophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide

Prepared as in Example 21b from(±)-3-((2-(2-cyano-3-nitrophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide(Example 129c) as a brown oil (29%). ¹H NMR (400 MHz, DMSO-d₆) δ1.13-1.19 (m, 6H), 1.42-1.66 (m, 6H), 2.02-2.07 (m, 2H), 3.74 (s, 3H),4.08 (m, 1H), 4.47 (m, 1H), 4.57 (m, 1H), 5.93 (brs, 2H), 6.32 (d, J=8.0Hz, 1H), 6.38 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 7.48-7.50 (m, 2H), 7.98 (d, J=8.0 Hz, 1H). MS 424 (MH⁺).

Example 129c:(±)-3-((2-(2-cyano-3-nitrophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide

Prepared as in Example 126c from(±)-3-((2-hydroxycyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide (Example129d) and 2,6-dinitrobenzonitrile as a brown solid (100%). MS 454 (MH⁺).

Example 129d:(±)-3-((2-hydroxycyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide

Prepared as in Example 24a from(±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic acid (Example 129e)and propan-2-amine as a white solid (80%). ¹H NMR (400 MHz, DMSO-d6) δ1.14 (d, J=8.0 Hz, 6H), 1.25-1.30 (m, 4H), 1.61 (m, 2H), 1.85 (m, 2H),3.56 (m, 1H), 3.79 (s, 3H), 4.03-4.12 (m, 2H), 4.81 (d, J=4.0 Hz, 1H),6.98 (d, J=8.0 Hz, 1H), 7.45-7.49 (m, 2H), 8.01 (d, J=8.0 Hz, 1H). MS308 (MH⁺).

Example 129e: (±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic Acid

Prepared as in Example 1 from (±)-ethyl3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate (Example 129f) as awhite solid (100%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.23-1.25 (m, 4H), 1.59(brs, 2H), 1.88 (m, 2H), 3.53 (m, 1H), 3.72 (s, 3H), 3.92 (m, 1H), 4.73(d, J=4.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0 Hz, 1H), 7.48(d, J=4.0 Hz, 1H).

Example 129f: (±)-ethyl 3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate

To a solution of methyl 3-hydroxy-4-methoxybenzoate (210 mg, 1.15 mmol)and cyclohexane oxide (466 uL, 4.61 mmol) in ethanol (11 mL) was addedK₂CO₃ (637 mg, 4.61 mmol) at room temperature. The reaction mixture wasthen refluxed overnight then cooled down to room temperature, andevaporated under reduced pressure until a small amount of ethanolremained. The solution was diluted with DCM and successively washed with1N HCl and brine, dried over Na₂SO₄ filtered and evaporated underreduced pressure. The residue was purified by chromatography on silicagel (Eluent: 0-20% EtOAc/Hexanes) to afford (±)-ethyl3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate as a colorless oil (307mg, 91%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.16-1.34 (m, 7H), 1.61 (m, 2H),1.84-1.94 (m, 2H), 3.55 (m, 1H), 3.83 (s, 3H), 4.03 (m, 1H), 4.28 (q,J=8.0 Hz, 2H), 4.85 (d, J=4.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H),7.55-7.58 (m, 2H).

Example 130:4-amino-5-(cyclohexyloxy)-2-(hydroxymethyl)quinoline-3-carboxylic Acid

Prepared as in Example 1 from9-amino-8-(cyclohexyloxy)furo[3,4-b]quinolin-1 (3H)-one (Example 130a)as a tan powder (44%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27-1.46 (m, 2H),1.53-1.71 (m, 6H), 2.00-2.04 (m, 2H), 4.70 (m, 1H), 4.87 (s, 2H), 7.10(d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 8.74(brs, 1H), 11.90 (brs, 1H). MS 317 (MH⁺).

Example 130a: 9-amino-8-(cyclohexyloxy)furo[3,4-b]quinolin-1 (3H)-one

Prepared as in Example 2a from 2-amino-6-(cyclohexyloxy)benzonitrile(Example 36b) and ethyl 4-chloro-3-oxobutanoate as an orange solid(29%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.30-1.72 (m, 8H), 2.04-2.08 (m, 2H),4.70 (m, 1H), 5.26 (s, 2H), 7.09 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz,1H), 7.64 (m, 2H), 8.14 (brs, 1H). MS 299 (MH⁺).

Example 131:1-amino-3-methyl-6b,7,8,9,10,10a-hexahydrobenzofuro[2,3-f]quinoline-2-carboxylicAcid

Prepared as in Example 1 from ethyl1-amino-3-methyl-6b,7,8,9,10,10a-hexahydrobenzofuro[2,3-f]quinoline-2-carboxylate(Example 131a) as an off-white solid (28%). ¹H NMR (400 MHz, DMSO-d₆) δ1.35-1.48 (m, 4H), 1.87-1.97 (m, 4H), 2.76 (s, 3H), 3.38 (m 1H), 5.03 (m1H), 7.20 (d, J=8 Hz, 1H), 7.61 (d, J=8 Hz, 1H). MS 299 (MH⁺).

Example 131a: ethyl1-amino-3-methyl-6b,7,8,9,10,10a-hexahydrobenzofuro[2,3-f]quinoline-2-carboxylate

Prepared as in Example 2a from2-amino-6-(cyclohex-2-en-1-yloxy)benzonitrile (Example 131b) and ethyl3-oxobutanoate as a pale yellow solid (11%). MS 327 (MH⁺).

Example 131b: 2-amino-6-(cyclohex-2-en-1-yloxy)benzonitrile

Prepared as in Example 22b from cyclohex-2-enol and2-amino-6-fluorobenzonitrile as a colorless oil (78%). ¹H NMR (400 MHz,CDCl₃) δ 1.64 (m, 1H), 1.96 (m, 4H), 2.15 (m, 1H), 4.39 (s, 2H), 4.82(m, 1H), 5.87 (m, 1H), 5.98 (m, 1H), 6.30 (d, 2H), 7.20 (t, 1H). MS 215(MH⁺).

Example 132: 4-amino-3-carboxy-5-(cyclohexyloxy)-2-methylquinoline1-oxide

Prepared as in Example 1 from4-(N-acetylacetamido)-5-(cyclohexyloxy)-3-(ethoxycarbonyl)-2-methylquinoline1-oxide (Example 132a) as a white solid (38%). ¹H NMR (400 MHz, DMSO-d₆)δ 1.31-1.68 (m, 8H), 1.98-2.04 (m, 2H), 2.69 (s, 3H), 4.71 (m, 1H), 7.20(d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.75(brs, 2H). MS 317 (MH⁺).

Example 132a:4-(N-acetylacetamido)-5-(cyclohexyloxy)-3-(ethoxycarbonyl)-2-methyl-quinoline1-oxide

To a solution of ethyl4-(N-acetylacetamido)-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate(Example 132b, 100 mg, 0.24 mmol) in DCE (5 mL) was added mCPBA (163 mg,0.73 mmol). The reaction mixture was stirred at room temperatureovernight under N₂. The solvent was removed under reduce pressure, andthe residue was purified by chromatography on silica gel eluting with0-100% EtOAc/Hexanes gradient to give the title compound as an orangeoil (100 mg, 97%). MS 429 (MH⁺).

Example 132b: ethyl4-(N-acetylacetamido)-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate

To a solution of ethyl4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a,700 mg, 2.13 mmol) and Et₃N (891 uL, 6.39 mmol) in DCM (20 mL) was addedacetyl chloride (455 uL, 6.39 mmol) at 0° C., and the reaction mixturewas stirred at 0° C.-RT overnight. The reaction was diluted with DCM andwashed successively with 10% citric acid, saturated NaHCO₃, H₂O, andbrine, dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica geleluting with 0-40% EtOAc/Hexanes gradient to afford the title compoundas a yellow oil (100 mg, 11%). MS 413 (MH⁺).

Example 133:4-amino-5-((2,3-dihydroxycyclohexyl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)cyclohexane-1,2-diyldiacetate (Example 133a) as a white solid (74%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.42-1.50 (m, 3H), 1.66-1.70 (m, 2H), 2.12-2.15 (m, 1H), 2.74(s, 3H), 3.71-3.73 (m, 1H), 3.90 (s, 1H), 4.60-4.62 (m, 1H), 4.71 (brs,1H), 5.18 (brs, 1H), 7.06 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.60(t, J=8.4 Hz, 1H). MS 333 (MH⁺).

Example 133a:3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)cyclohexane-1,2-diyldiacetate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)cyclohexane-1,2-diyl diacetate (Example 133b)and ethyl 3-oxobutanoate as a pale yellow solid (32%). MS 445 (MH⁺).

Example 133b: 3-(3-amino-2-cyanophenoxy)cyclohexane-1,2-diyl diacetate

Prepared as in Example 21b from3-(2-cyano-3-nitrophenoxy)cyclohexane-1,2-diyl diacetate (Example 133c)as a white solid (84%). MS 333 (MH⁺).

Example 133c: 3-(2-cyano-3-nitrophenoxy)cyclohexane-1,2-diyl Diacetate

Prepared as in Example 132b from2-((2,3-dihydroxycyclohexyl)oxy)-6-nitrobenzonitrile (Example 133d) andacetyl chloride as a white solid (19%). MS 363 (MH⁺).

Example 133d: 2-((2,3-dihydroxycyclohexyl)oxy)-6-nitrobenzonitrile

To a solution of 2-(cyclohex-2-en-1-yloxy)-6-nitrobenzonitrile (Example133e, 5.3 g, 21.7 mmol) in THF/H₂O (1:1 by volume, 110 mL) was addedOsO₄ (110.3 mg, 0.434 mmol) at room temperature. After it was stirredfor 30 minutes, NaClO₃ (2.71 g, 26.04 mmol) was added in small portionsover a period of 1 h, and the reaction mixture was stirred at roomtemperature for 48 h. The reaction was carefully quenched with aqueoussodium bisulfite solution, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was purified by chromatography on silica geleluting with 80-100% EtOAc in hexanes to give the title compound as abrown solid (3.88 g, 64%). MS 279 (MH⁺).

Example 133e: 2-(cyclohex-2-en-1-yloxy)-6-nitrobenzonitrile

Prepared as in Example 126c from cyclohex-2-enol and2,6-dinitrobenzonitrile as a brown solid (90%). MS 245 (MH⁺).

Example 134:4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

To a solution of ethyl4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 134a, 14.0 g, 36.2 mmol) in EtOH (140 mL) was added aqueousNaOH solution (2.0 N, 46 mL) at room temperature. The reaction mixturewas stirred at 90° C. for 4 hrs. The resulting solution was neutralizedat 0° C. to pH 7 with 6 N HCl, and concentrated under reduced pressure.The residue was re-dissolved in EtOH (400 mL) and water (25 mL), andtreated with charcoal (200 mg) at 65° C. for 30 minutes. After removalof the charcoal by filtration, the filtrate was concentrated, and theresultant white solid was purified by re-crystallization from EtOH/H₂Oand dried under vacuum at 70° C. to give the title compound as a whitesolid (11.5 g, 89%). M.p.: 216-218° C. ¹H NMR (400 MHz, DMSO-d₆) δ 1.01(d, J=6.4 Hz, 6H), 1.24 (s, 6H), 2.75 (s, 3H), 3.86-3.93 (m, 1H), 4.17(s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 8.83 (brs, 1H), 12.34 (brs, 1H), 12.78(brs, 1H). MS 360 (MH⁺).

Example 134a: ethyl4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Method A: to a solution of3-(3-amino-2-cyanophenoxy)-N-isopropyl-2,2-dimethylpropanamide (Example134b, 11.35 g, 41.27 mmol) and ethyl 3-oxobutanoate (5.2 mL, 41.27 mmol)in anhydrous 1,2-dichloroethane (110 mL) and toluene (110 mL) was addeddropwise SnCl₄ (9.66 mL, 82.55 mmol) at room temperature under nitrogen.The reaction mixture was heated to reflux for 3 hrs. The solution wascooled to room temperature and the solvent removed under reducedpressure. The residue was dissolved in EtOAc (600 mL) and neutralized at0° C. to pH 8 with 6 N NaOH. The organic layer was separated and theaqueous layer was further extracted with EtOAc (100 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andevaporated. The residue was purified by chromatography on Biotage SP-1,40S x4 column eluting with 0-5% MeOH in dichloromethane, andre-crystallized from EtOAc to give the title compound as a cream whitesolid (14.0 g, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H),1.24 (s, 6H), 1.32 (t, J=7.2 Hz, 3H), 2.55 (s, 3H), 3.87-3.93 (m, 1H),4.12 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 6.87 (d, J=7.2 Hz, 1H), 7.23 (d,J=8.4 Hz, 1H), 7.49-7.53 (m, 3H), 8.09 (s, 2H). MS 388 (MH⁺).

Method B: to a solution of3-(3-amino-2-cyanophenoxy)-N-isopropyl-2,2-dimethylpropanamide (Example134b, 10.0 g, 36.4 mmol) in ethyl 3-oxobutanoate (110 mL, 874 mmol, 24eq.) was added anhydrous FeCl₃ (6.5 g, 40 mmol, 1.1 eq.) at roomtemperature under nitrogen. The black reaction mixture was stirred for 2h at 110° C. Excess of ethyl 3-oxobutanoate was rotary evaporated at 80°C. The thick resulting mixture was dissolved in EtOAc (200 mL). Anaqueous solution of NaOH (15%) (80 ml) was slowly added at 0° C. Themixture was stirred for 15 min. The organic layer was separated and theaqueous solution was extracted once more with EtOAc (100 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄. Afterevaporation of the solvent, the residue was purified by chromatographyon silica gel eluting with 5-10% MeOH in DCM, and re-crystallized fromEtOAc to give the title compound as an off-white solid (5.57 g, 40%).

Example 134b:3-(3-amino-2-cyanophenoxy)-N-isopropyl-2,2-dimethylpropanamide

To a solution of 3-hydroxy-N-isopropyl-2,2-dimethylpropanamide (Example134c, 5.12 g, 32.15 mmol) in dry THF (100 mL) was added portion-wise NaH(60% in mineral oil, 1.41 g, 35.37 mmol) at 0° C. under nitrogen. Thereaction mixture was stirred at 0° C. for about 30 minutes untilbubbling ceased. 2-Amino-6-fluorobenzonitrile (4.38 g, 32.15 mmol) wasadded and the solution stirred at 80° C. overnight. The reaction mixturewas quenched slowly with water at 0° C., and concentrated under reducedpressure. The residue was taken up in EtOAc and washed consecutivelywith brine and water, dried over Na₂SO₄ and concentrated. The residuewas purified by re-crystallization from EtOAc/hexane to give the titlecompound as a white crystalline solid (4.4 g, 50%). ¹H NMR (400 MHz,CDCl₃) δ 1.18 (d, J=6.8 Hz, 6H), 1.32 (s, 6H), 3.94 (s, 2H), 4.04-4.12(m, 1H), 4.43 (s, 2H), 5.98 (d, J=6.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H),6.32 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H). MS 276 (MH⁺).

Example 134c: 3-hydroxy-N-isopropyl-2,2-dimethylpropanamide

Method A: to a Parr Reactor was added methyl3-hydroxy-2,2-dimethylpropanoate (66.0 g, 0.5 mol) and propan-2-amine(59.1 g, 1.0 mol) at room temperature. The reaction mixture was thenstirred at 190° C. overnight. The reaction was cooled to roomtemperature and the solution concentrated under reduced pressure. Theresidue was dissolved in EtOAc and the solution successively washed withbrine (5×), dried over Na₂SO₄, and evaporated under reduced pressure.The residue was co-evaporated with dry toluene (100 mL×2) to give thetitle compound as a colorless oil (38.76 g, 49%). ¹H NMR (400 MHz,DMSO-d₆) δ 0.98 (s, 6H), 1.02 (d, J=6.4 Hz, 6H), 3.32 (d, J=5.2 Hz, 2H),3.79-3.88 (m, 1H), 4.83 (t, J=5.2 Hz, 1H), 7.11 (d, J=7.2 Hz, 1H). MS160 (MH⁺).

Method B: to a solution of propan-2-amine (9.7 mL, 113.0 mmol) and3-hydroxy-2,2-dimethylpropanoic acid (11.1 g, 94.2 mmol) indichloromethane (500 mL) was added1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (22.0 g,113 mmol), 1-hydroxybenzotriazole monohydrate (17.3 g, 113 mmol), andtriethylamine (16 mL, 113 mmol). The reaction was stirred at roomtemperature overnight. The crude mixture was concentrated on therotovap. The residue was taken up in EtOAc and washed with saturatedNaHCO₃, brine, and water. The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure to afford the tilecompound as a clear oil (5.12 g, 34%). MS 160 (MH⁺).

Example 135:4-amino-5-(3-(cyclopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 135a) as a white solid (60%). M.p.: 227-229° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.40-0.44 (m, 2H), 0.58-0.62 (m, 2H), 1.24 (s, 6H), 2.62(m, 1H), 2.77 (s, 3H), 4.15 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.30 (d,J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H), 8.75(brs, 1H), 12.25 (brs, 1H), 12.77 (brs, 1H). MS 358 (MH⁺).

Example 135a: ethyl4-amino-5-(3-(cyclopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclopropanamine as a pale yellow solid (64%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.14-0.45 (m, 2H), 0.57-0.62 (m, 2H), 1.25 (s,6H), 1.35 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 2.62-2.65 (m, 1H), 4.13 (s,2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, 1H), 7.27 (d, 1H), 7.53 (t, J=8.0Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 8.09 (s, 2H). MS 386 (MH⁺).

Example 136:4-amino-5-(3-(cyclobutylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclobutylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 136a) as a white solid (45%). M.p.: 183-187° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.24 (s, 6H), 1.52-1.63 (m, 2H), 1.87-1.98 (m, 2H),2.03-2.12 (m, 2H), 2.75 (s, 3H), 4.16 (s, 2H), 4.17-4.26 (m, 1H), 7.01(d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.97(d, J=8.0 Hz, 1H), 8.78 (brs, 1H), 12.35 (brs, 1H), 12.70 (brs, 1H). MS372 (MH⁺).

Example 136a: ethyl4-amino-5-(3-(cyclobutylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclobutanamine as an off-white solid (71%). MS400 (MH⁺).

Example 137:4-amino-5-(((1,4)-trans-4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(((1,4)-trans-4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 137a) as a white solid (86%). M.p.: 183-185° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.95 (s, 3H), 0.97 (s, 3H), 1.34-1.38 (m, 2H), 1.65-1.68(m, 2H), 1.81-1.84 (m, 2H), 2.13-2.15 (m, 2H), 2.29-2.34 (m, 1H), 2.75(s, 3H), 3.57-3.59 (m, 1H), 4.64 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.26(d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.65 (m, 2H). MS 386 (MH⁺).

Example 137a: ethyl4-amino-5-(((1,4)-trans-4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-((1,4)-trans-4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide(Example 137b) and ethyl acetoacetate as an off-white solid (88%). MS414 (MH⁺).

Example 137b:N-((1,4)-trans-4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide

Prepared as in Example 22a fromN-((1,4)-trans-4-hydroxycyclohexyl)isobutyramide (Example 137c) and2-amino-6-fluorobenzonitrile as an off-white solid (91%). MS 302 (MH⁺).

Example 137c: N-((1,4)-trans-4-hydroxycyclohexyl)isobutyramide

Prepared as in Example 24a from isobutyric acid and(1,4)-trans-4-aminocyclohexanol as a colorless oil (51%). MS 186 (MH⁺).

Example 138:4-amino-2-methyl-5-(2-methyl-2-(3-methylbutanamido)propoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-(3-methylbutan-amido)propoxy)quinoline-3-carboxylate(Example 138a) as a white solid (47%). M.p.: 195-198° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.50 (d, J=4.0 Hz, 6H), 1.37 (s, 6H), 1.90-2.0 (m, 3H),2.73 (s, 3H), 4.32 (s, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz,1H), 7.57 (t, J=8.0 Hz, 1H), 8.45 (s, 1H), 11.14 (brs, 1H), 12.94 (brs,1H). MS 374 (MH⁺).

Example 138a: ethyl4-amino-2-methyl-5-(2-methyl-2-(3-methylbutanamido)propoxy)-quinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-methylbutanoic acid as an off-white solid (100%). MS402 (MH⁺).

Example 139:4-amino-5-(2-isobutyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-isobutyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 139a) as a white solid (38%). M.p.: 184-186° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.89 (d, J=8.0 Hz, 6H), 1.35 (s, 6H), 2.41 (m, 1H), 2.79(s, 3H), 4.35 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H),7.65 (t, J=8.0 Hz, 1H), 7.82 (s, 1H), 8.83 (brs, 1H), 12.10 (brs, 1H),13.10 (brs, 1H). MS 360 (MH⁺).

Example 139a: ethyl4-amino-5-(2-isobutyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and isobutyric acid as a white solid (58%). MS 388 (MH⁺).

Example 140:4-amino-2-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-4-carboxamido)-propoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-4-carboxamido)propoxy)quinoline-3-carboxylate(Example 140a) as a white solid (65%). M.p.: 170-173° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.35 (s, 6H), 1.44-1.49 (m, 4H), 2.40 (m, 1H), 2.76 (s,3H), 3.19-3.25 (m, 2H), 3.75-3.79 (m, 2H), 4.34 (s, 2H), 6.99 (d, J=8.0Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.84 (s, 1H).MS 402 (MH⁺).

Example 140a: ethyl4-amino-2-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-4-carbox-amido)propoxy)quinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and tetrahydro-2H-pyran-4-carboxylic acid as a pale-yellowsolid (63%). MS 430 (MH⁺).

Example 141:4-amino-2-methyl-5-(2-methyl-2-propionamidopropoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-propionamido-propoxy)quinoline-3-carboxylate(Example 141a) as a white solid (31%). M.p.: 189-193° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.89 (t, J=8.0 Hz, 6H), 1.34 (s, 6H), 2.05 (q, J=8.0 Hz,2H), 2.72 (s, 3H), 4.31 (s, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.80 (s, 1H), 8.41 (brs, 1H), 11.02(brs, 1H), 13.17 (brs, 1H). MS 346 (MH⁺).

Example 141a: ethyl4-amino-2-methyl-5-(2-methyl-2-propionamidopropoxy)quinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and propionic acid as a pale-yellow solid (23%). MS 374(MH⁺).

Example 142:4-amino-5-(2-(cyclobutanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2-(cyclobutanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 142a) as a white solid (65%). M.p.: 186-190° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.34 (s, 6H), 1.56-1.66 (m, 1H), 1.73-1.84 (m, 1H),1.87-2.03 (m, 4H), 2.78 (s, 3H), 3.00-3.08 (m, 1H), 4.36 (s, 2H), 7.01(d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.73(s, 1H), 8.76 (brs, 1H), 12.01 (brs, 1H), 13.05 (brs, 1H). MS 372 (MH⁺).

Example 142a: ethyl4-amino-5-(2-(cyclobutanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and cyclobutanecarboxylic acid as an off-white solid(61%). MS 400 (MH⁺).

Example 143:4-amino-5-((1-isobutyrylpiperidin-4-yl)oxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-((1-isobutyrylpiperidin-4-yl)oxy)-2-methylquinoline-3-carboxylate(Example 143a) as a white solid (88%). M.p.: 184-186° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.95 (s, 3H), 0.99 (t, 6H), 1.68-1.82 (m, 2H), 2.02-2.11(m, 2H), 2.74 (s, 3H), 2.89 (m, 1H), 3.01 (m, 1H), 3.35 (m, 1H), 3.84(m, 1H), 4.04 (m, 1H), 4.94 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.26 (d,J=7.6 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H). MS 372 (MH⁺).

Example 143a: ethyl4-amino-5-((1-isobutyrylpiperidin-4-yl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-isobutyrylpiperidin-4-yl)oxy)benzonitrile (Example 143b)and ethyl acetoacetate as an off-white solid (82%). MS 400 (MH⁺).

Example 143b: 2-amino-6-((1-isobutyrylpiperidin-4-yl)oxy)benzonitrile

Prepared as in Example 22a from1-(4-hydroxypiperidin-1-yl)-2-methylpropan-1-one (Example 143c) and2-amino-6-fluorobenzonitrile as an off-white solid (87%). MS 288 (MH⁺).

Example 143c: 1-(4-hydroxypiperidin-1-yl)-2-methylpropan-1-one

Prepared as in Example 24a from isobutyric acid and piperidin-4-ol as acolorless oil (43%). MS 172 (MH⁺).

Example 144:4-amino-5-(3-(ethylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(ethylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 144a) as a white solid (75%). M.p.: 168-170° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.96 (t, J=8 Hz, 3H), 1.24 (s, 6H), 3.06 (s, 3H), 3.09(dq, J=1.6, 8.0 Hz, 2H), 4.14 (s, 2H), 7.00 (d, J=8.0 Hz, 1H), 7.26 (d,J=8.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.90 (t, J=8.0 Hz, 1H), 8.85(brs, 1H), 12.32 (brs, 1H), 12.70 (brs, 1H). MS 346 (MH⁺).

Example 144a: ethyl4-amino-5-(3-(ethylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and ethylamine hydrochloride as an off-white solid(61%). MS 374 (MH⁺).

Example 145:4-amino-2-methyl-5-(2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)acetamido)-propoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)acetamido)propoxy)quinoline-3-carboxylate(Example 145a) as a white solid (28%). M.p.: 175-178° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.06-1.13 (m, 2H), 1.35-1.38 (m, 8H), 1.79 (m, 1H), 1.98(d, J=4.0 Hz, 2H), 2.77 (s, 3H), 3.10 (t, J=4.0 Hz, 2H), 3.60 (m, 2H),4.34 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.65 (t,J=8.0 Hz, 1H), 7.88 (s, 1H), 8.76 (brs, 1H), 12.43 (brs, 1H), 12.71(brs, 1H). MS 416 (MH⁺).

Example 144a: ethyl4-amino-2-methyl-5-(2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)acetamido)propoxy)quinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid as a yellowsolid (37%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.05-1.08 (m, 2H), 1.30-1.38(m, 11H), 1.79 (m, 1H), 1.97 (d, J=4.0 Hz, 2H), 2.56 (s, 3H), 3.07 (t,J=8.0 Hz, 2H), 3.61 (d, J=8.0 Hz, 2H), 4.28-4.34 (m, 4H), 6.87 (d, J=8.0Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.73 (s, 1H),8.21 (s, 2H). MS 444 (MH⁺).

Example 146:4-amino-5-(3-((cyclopropylmethyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-((cyclopropylmethyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 146a) as a white solid (39%). M.p.: 177-179° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.12-0.13 (m, 2H), 0.30-0.31 (m, 2H), 0.89 (m, 1H), 1.28(s, 6H), 2.76 (s, 3H), 2.98 (t, J=4.0 Hz, 2H), 4.17 (s, 2H), 7.03 (d,J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.98 (t,J=8.0 Hz, 1H), 8.80 (brs, 1H), 12.26 (brs, 1H), 12.76 (brs, 1H). MS 372(MH⁺).

Example 146a: ethyl4-amino-5-(3-((cyclopropylmethyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclopropylmethanamine as a pale-yellow solid(80%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.12-0.13 (m, 2H), 0.29-0.31 (m, 2H),0.90 (m, 1H), 1.27 (s, 6H), 1.33 (t, J=8.0 Hz, 3H), 2.56 (s, 3H), 2.97(t, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.88 (d, J=8.0Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.91 (t, J=4.0Hz, 1H), 8.11 (s, 2H). MS 400 (MH⁺).

Example 147:4-amino-5-(3-(butylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(butylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 147a) as an off-white solid (59%). M.p.: 195-199° C. ¹H NMR(400 MHz, DMSO-d₆) δ 0.74 (t, J=8.0 Hz, 3H), 1.11-1.21 (m, 2H), 1.27 (s,6H), 1.32-1.39 (m, 2H), 2.77 (s, 3H), 3.09 (q, J=8.0 Hz, 2H), 4.17 (s,2H), 7.03 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz,1H), 7.88 (t, J=8.0 Hz, 1H), 8.87 (brs, 1H), 12.41 (brs, 1H), 12.74(brs, 1H). MS 374 (MH⁺).

Example 147a: ethyl4-amino-5-(3-(butylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and n-butylamine as a pale-yellow solid (91%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.74 (t, J=8.0 Hz, 3H), 1.15-1.20 (m, 2H), 1.27 (s,6H), 1.32-1.38 (m, 5H), 2.57 (s, 3H), 3.06-3.11 (q, J=8.0 Hz, 2H), 4.14(s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 8.10 (s, 2H).MS 402 (MH⁺).

Example 148:4-amino-5-(2,2-dimethyl-3-oxo-3-(pentan-3-ylamino)propoxy)-2-methyl-quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-(pentan-3-ylamino)propoxy)-2-methylquinoline-3-carboxylate(Example 148a) as a white solid (72%). M.p.: 172-174° C. ¹H NMR (400MHz, DMSO-d₆) δ 0.69 (t, J=8.0 Hz, 6H), 1.29 (s, 6H), 1.32-1.42 (m, 4H),2.76 (s, 3H), 3.59-3.64 (m, 1H), 4.21 (s, 2H), 7.03 (d, J=8.0 Hz, 1H),7.29 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H),8.79 (brs, 1H), 12.35 (brs, 1H), 12.73 (brs, 1H). MS 388 (MH⁺).

Example 148a: ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-(pentan-3-ylamino)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and pentan-3-amine as a pale-yellow solid (78%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.68 (t, J=8.0 Hz, 6H), 1.27 (s, 6H), 1.31 (t,J=8.0 Hz, 3H), 1.37-1.42 (m, 4H), 2.54 (s, 3H), 3.56-3.61 (m, 1H), 4.16(s, 2H), 4.30 (q, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.06 (s, 2H).MS 416 (MH⁺).

Example 149:4-amino-2-methyl-5-(2-methyl-2-(2-morpholinoacetamido)propoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-(2-morpholino-acetamido)propoxy)quinoline-3-carboxylate(Example 149a) as a white solid (32%). M.p.: 173-175° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.39 (s, 6H), 2.35 (t, J=4.8 Hz, 4H), 2.74 (s, 3H), 2.85(s, 2H), 3.47 (t, J=4.8 Hz, 4H), 4.35 (s, 2H), 7.00 (d, J=8.0 Hz, 1H),7.27 (d, J=8.4 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.71 (s, 1H). MS 417(MH⁺).

Example 149a: ethyl4-amino-2-methyl-5-(2-methyl-2-(2-morpholinoacetamido)pro-poxy)quinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 2-morpholinoacetic acid as a yellow solid (37%). MS445 (MH⁺).

Example 150:4-amino-5-(3-(isobutylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-(isobutylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 150a) as an off-white solid (60%). M.p.: 176-179° C. ¹H NMR(400 MHz, DMSO-d₆) δ 0.73 (d, J=6.8 Hz, 6H), 1.27 (s, 6H), 1.65-1.75 (m,1H), 2.77 (s, 3H), 2.89 (t, J=6.4 Hz, 2H), 4.17 (s, 2H), 7.01 (d, J=8.4Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.90 (t, J=5.8Hz, 1H), 8.84 (brs, 1H), 12.16 (brs, 1H), 12.91 (brs, 1H). MS 374 (MH⁺).

Example 150a: ethyl4-amino-5-(3-(isobutylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and isobutylamine as an off-white solid (82%). MS 402(MH⁺).

Example 151:4-amino-5-(3-((cyclobutylmethyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-5-(3-((cyclobutylmethyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 151a) as a white solid (54%). M.p.: 170-172° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.26 (s, 6H), 1.54-1.71 (m, 4H), 1.76-1.84 (m, 2H),2.35-2.42 (m, 1H), 2.76 (s, 3H), 3.10 (t, J=6.0 Hz, 2H), 4.18 (s, 2H),7.13 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H),7.87 (t, J=6.4 Hz, 1H), 9.21 (brs, 1H), 10.92 (brs, 1H). MS 386 (MH⁺).

Example 151a: ethyl4-amino-5-(3-((cyclobutylmethyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclobutylmethanamine as an off-white solid(67%). MS 414 (MH⁺).

Example 152:5-(2-(6-Ammoniohexanamido)-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminiumTrifluoroacetate

A solution of4-amino-5-(2-(6-(tert-butoxycarbonylamino)hexanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid (Example 152a) (59.6 mg, 0.12 mmol) in CH₂Cl₂ (9.0 mL) was treatedwith trifluoroacetic acid (1.0 mL) at room temperature. After beingstirred at room temperature for 2 h the reaction mixture was evaporatedto dryness. The residue was dissolved in H₂O (5.0 mL) and the productwas isolated by preparative HPLC (RPC18, H₂O→CH₃CN gradient). Theappropriate fractions were collected and evaporated under reducedpressure. The residue was dried in a dessicator over phosphoruspentoxide to give 43.6 mg (58%) of5-(2-(6-ammoniohexanamido)-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminiumtrifluoroacetate as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.56 (s,1H), 9.98 (s, 1H), 9.40 (s, 1H), 7.88 (t, J=8.3 Hz, 1H), 7.75 (s, 1H),7.72-7.56 (m, 3H), 7.42 (d, J=7.9 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 4.42(s, 2H), 2.81 (s, 3H), 2.72-2.60 (m, 2H), 2.08 (t, J=7.3 Hz, 2H),1.50-1.39 (m, 4H), 1.38 (s, 6H), 1.26-1.14 (m, 2H). MS 404 (M+).

Example 152a:4-Amino-5-(2-(6-(tert-butoxycarbonylamino)hexanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicAcid

A solution of 6-(tert-butoxycarbonylamino)hexanoic acid (0.21 g, 0.90mmol) in dry DMF (10 mL) was treated with triethylamine (0.46 g, 4.51mmol, 0.63 mL) and N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uroniumtetrafluoroborate (TSTU) (0.30 g, 0.99 mmol) at room temperature under anitrogen atmosphere. The reaction mixture was stirred at roomtemperature over 3 h and then a solution of5-(2-ammonio-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminiumchloride (Example 152b) (0.33 g, 0.90 mmol) and triethylamine (0.46 g,4.51 mmol, 0.63 mL) in dry DMF was added dropwise at room temperature.The obtained mixture was stirred at room temperature over 3 days and thesolvent was evaporated. The residue was dissolved in a mixture of MeOHand H₂O (50 mL, 1:1) and the product was isolated by preparative HPLC(RPC18, H₂O→CH₃CN gradient). The appropriate fractions were collectedand evaporated under reduced pressure. The residue was dried in adessicator over phosphorus pentoxide to give 0.21 g (45%) of4-amino-5-(2-(6-(tert-butoxycarbonylamino)hexanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95-12.65 (m, 1H),12.45-11.95 (m, 1H), 9.05-8.60 (m, 1H), 7.84 (s, 1H), 7.67 (t, J=8.0 Hz,1H), 7.29 (d, J=8.2 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.71 (t, J=5.6 Hz,1H), 4.36 (s, 2H), 2.78 (s, 3H), 2.70 (q, J=6.4 Hz, 2H), 2.05 (t, J=7.3Hz, 2H), 1.45-1.34 (m, 2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.30-1.19 (m,2H), 1.14-1.03 (m, 2H). MS 503 (MH⁺).

Example 152b:5-(2-Ammonio-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminiumChloride

To a solution of ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) (0.65 g, 2.05 mmol) in EtOH (35 mL) was added a solutionof NaOH in H₂O (2.0 M, 5.2 mL) at room temperature under a nitrogenatmosphere. The obtained reaction mixture was heated at 80° C. over 3 hand cooled to room temperature. The pH of the cold mixture was adjustedto 1 with a solution of HCl (1.5 M) and the acidified solution wasevaporated to dryness. The residue was dissolved in a mixture of EtOHand H₂O (30 mL, 1:1) and the product was isolated by preparative HPLC(RPC18, H₂O→CH₃CN gradient). The appropriate fractions were collectedand evaporated under reduced pressure. The residue was dried in adessicator over phosphorus pentoxide to give 0.41 g (54%)5-(2-ammonio-2-methylpropoxy)-3-carboxy-2-methylquinolin-4-aminiumchloride as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.05-9.90 (m,1H), 9.15-9.00 (m, 1H), 8.69-8.57 (m, 3H), 7.91 (t, J=8.3 Hz, 1H), 7.65(d, J=8.0 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 4.39 (s, 2H), 2.84 (s, 3H),1.44 (s, 6H). MS 291 (M⁺)

Example 153:4-amino-2-methyl-5-((1-propionylpiperidin-4-yl)methoxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-((1-propionylpiperidin-4-yl)methoxy)quinoline-3-carboxylate(Example 153a) as an off-white solid (55%). M.p.: 168-170° C. ¹H NMR(400 MHz, DMSO-d₆) δ 0.96 (t, J=7.6 Hz, 3H), 1.08-1.25 (m, 2H), 1.81 (t,J=15.6 Hz, 2H), 2.19-2.26 (m, 1H), 2.30 (q, J=7.2 Hz, 2H), 2.55 (t, J=12Hz, 1H), 2.75 (s, 3H), 3.01 (t, J=12 Hz, 1H), 3.88 (d, J=13.6 Hz, 1H),4.1 (d, J=5.6 Hz 2H), 4.42 (d, J=13.2 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H),7.27 (d, J=7.6 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H). MS 372 (MH⁺).

Example 153a: ethyl4-amino-2-methyl-5-((1-propionylpiperidin-4-yl)methoxy)quinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-propionylpiperidin-4-yl)methoxy)benzonitrile (Example153b) and ethyl acetoacetate as an off-white solid (41%). MS 400 (MH⁺).

Example 153b: 2-amino-6-((1-propionylpiperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 22a from1-(4-(hydroxymethyl)piperidin-1-yl)propan-1-one (Example 153c) and2-amino-6-fluorobenzonitrile as a pale-yellow solid (15%). MS 288 (MH⁺).

Example 153c: 1-(4-(hydroxymethyl)piperidin-1-yl)propan-1-one

Prepared as in Example 24a from propionyl chloride andpiperidin-4-ylmethanol as a colorless oil (40%). MS 172 (MH⁺).

Example 154:4-amino-2-methyl-5-(((1,4)-trans-4-(methylcarbamoyl)cyclohexyl)oxy)quinoline-3-carboxylicAcid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(((1,4)-trans-4-(methylcarbamoyl)cyclohexyl)oxy)quinoline-3-carboxylate(Example 154a) as a white solid (42%). M.p.: 195-198° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.55-1.80 (m, 6H), 2.00-2.10 (m, 2H), 2.20-2.30 (m, 1H),2.55 (d, J=8.0 Hz, 3H), 2.76 (s, 3H), 4.96 (s, 1H), 7.07 (d, J=8.0 Hz,1H), 7.27 (d, J=8.0 Hz, 1H), 7.66-7.72 (m, 1H), 8.76 (brs, 1H), 12.00(brs, 1H), 12.83 (brs, 1H). MS 358 (MH⁺).

Example 154a: ethyl4-amino-2-methyl-5-(((1,4)-trans-4-(methylcarbamoyl)cyclohexyl-)oxy)quinoline-3-carboxylate

Prepared as in Example 2a from(1,4)-trans-4-(3-amino-2-cyanophenoxy)-N-methylcyclohexanecarboxamide(Example 154b) and ethyl acetoacetate as a yellow solid (43%). MS 386(MH⁺).

Example 154b:(1,4)-trans-4-(3-amino-2-cyanophenoxy)-N-methylcyclohexanecarboxamide

Prepared as in Example 47c from4-(2-cyano-3-nitrophenoxy)-N-methylcyclohexanecarboxamide (Example 154c)as pale-yellow solid (41%). MS 274 (MH⁺).

Example 154c: 4-(2-cyano-3-nitrophenoxy)-N-methylcyclohexanecarboxamide

Prepared as in Example 24a from4-(2-cyano-3-nitrophenoxy)cyclohexanecarboxylic acid (Example 154d) andmethylamine hydrochloride as an orange solid (80%). MS 304 (MH⁺).

Example 154d: 4-(2-cyano-3-nitrophenoxy)cyclohexanecarboxylic Acid

Prepared as in Example 47d from 4-hydroxycyclohexanecarboxylic acid and2,6-dinitrobenzonitrile as a brown solid (50%). MS 291 (MH⁺).

Example 155:4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicAcid Phosphate

Prepared as in Example 127 from4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicacid (Example 134) and H₃PO₄ as a white solid (100%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H), 1.25 (s, 6H), 2.76 (s, 3H), 3.86-3.95(m, 1H), 4.17 (s, 2H), 7.04 (d, J=8.0 Hz, 1H), 7.30 (dd, J=8.0 Hz, 0.8Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H). MS 360(MH⁺+H—H₃PO₄).

Example 156: sodium4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 128 from4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicacid (Example 134) and NaHCO₃ as a white solid (100%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H), 1.23 (s, 6H), 2.56 (s, 3H), 3.86-3.94(m, 1H), 4.07 (s, 2H), 6.66 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H),7.32 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 360 (MH⁺+H-Na).

The following compounds in Table G were synthesized by following theprocedures described above.

TABLE G Compound No. Compound MS (MH+) G-1

416 G-2

372 G-3

372 G-4

318 G-5

332 G-6

344 G-7

372 G-8

400 G-9

400 G-10

497 G-11

398 G-12

386 G-13

348 G-14

372 G-15

415 G-16

348 G-17

416 G-18

416 G-19

386

Example 157:N⁵-isopropyl-1H-benzo[c][1,2,6]thiadiazine-4,5-diamine-2,2-dioxide

A solution of 2-amino-6-(isopropylamino)benzonitrile sulfamide (Example157a) (0.14 g, 0.54 mmol) and NaOH (2 N, 0.54 mL) in EtOH (3 mL) wasstirred at 90° C. under nitrogen for 0.5 hour. The reaction mixture wascooled to room temperature, and concentrated under vacuum. H₂O (1 mL)was added and the reaction mixture was neutralized to pH ˜3 with 10%AcOH. The resultant precipitate was extracted with EtOAc, and afterevaporation of solvents the residue was purified by preparative thinlayer chromatography using a DCM/EtOAc (4:1) solution as eluant, to giveN⁵-isopropyl-1H-benzo[c][1,2,6]thiadiazine-4,5-diamine-2,2-dioxide (0.02g). ¹H NMR (400 MHz, DMSO-d₆) δ 1.11 (d, J=6.4 Hz, 6H), 1.84 (bs, 1H),5.24 (bs, NH), 6.22-6.19 (m, 2H, NH), 7.09 (t, J=8.0 Hz, 1H), 7.48 (bs,2H). MS 255 (MH⁺).

Example 157a: 2-amino-6-(isopropylamino)benzonitrile sulfamide

To a solution of 2-amino-6-(isopropylamino)benzonitrile (Example 157b)(0.09 g, 0.54 mmol) in DMA (3 mL) was added sulfamoyl chloride (0.19 g,1.62 mmol). The reaction mixture was stirred at room temperature undernitrogen for 2 hours, diluted with H₂O (5 mL) and extracted with EtOAc.Solvents of the combined organic phases were evaporated and the residuewas purified by preparative thin layer chromatography using aHexane/EtOAc (3:2) solution as eluant, to give2-amino-6-(isopropylamino)benzonitrile sulfamide (0.14 g). MS 255 (MH⁺).

Example 157b: 2-amino-6-(isopropylamino)benzonitrile

To a solution of 2-(isopropylamino)-6-nitrobenzonitrile (Example 157c)(0.21 g, 1.02 mmol) in MeOH (9 mL) was added concentrated HCl (2 mL).Then Fe (0.17 g, 3.07 mmol) was added portionwise, and the reactionmixture was refluxed at 90° C. for 15 minutes. After cooling to roomtemperature, dilution with H₂O (50 mL) and extraction with DCM (3×50mL), the combined organic phases were washed with brine, dried overMgSO₄ and the solvents were evaporated to give2-amino-6-(isopropylamino)benzonitrile (0.19 g, 100%) as a brown oilwhich was used in the next step without any further purification. MS 176(MH⁺).

Example 157c: 2-(isopropylamino)-6-nitrobenzonitrile

To a solution of 2,6-dinitrobenzonitrile (0.58 g, 3.00 mmol) in DMF (6mL) was added isopropylamine (0.71 g, 12.00 mmol) and the reactionmixture was stirred at 50° C. under nitrogen for ten minutes. Aftercooling to room temperature, dilution with H₂O and extraction withEtOAc, solvents of the combined organic phases were evaporated and theresidue was purified by flash chromatography (Biotage system, 80 gsilicagel column) using a Hexane/EtOAc (3:2) solution as eluant, to give2-(isopropylamino)-6-nitrobenzonitrile (0.22 g, 35%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.20 (d, J=6.4 Hz, 6H), 3.85-3.80 (m, 1H), 5.94 (d, J=8.0 Hz,NH), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.60 (t, J=8.8 Hz,1H).

Example 158:4-Amino-5-(propyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

To a suspension of 2-sulfamoylamino-6-propoxybenzonitrile (Example 158a)(4.73 g, 18.53 mmol) in ethanol (65 mL), was added aqueous NaOH (2N,18.6 ml, 37.06 mmol). The resulting clear solution was refluxed for 3hours under nitrogen. After cooling to room temperature, the resultingsolution was filtered, the filtrate was cooled to 0° C. and neutralizedwith 10% acetic acid. The resulting precipitate was collected byfiltration, suspended in 50 ml of ethanol/water (1:1) and warmed to 40°C. for 20 min. The solid was collected by filtration to provide4-Amino-5-(propyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (4 g,85%) as a pale yellow powder. M.p.: 229-230° C. ¹H NMR (400 MHz,DMSO-d₆) δ 0.96 (t, J=7.3 Hz, 3H), 1.81 (sext, J=7.3 Hz, 2H), 4.10 (t,J=6.7 Hz, 2H), 6.60 (d, J=8.6 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 7.44 (t,J=8.6 Hz, 1H), 7.81 (br s, 1H), 8.35 (br s, 1H), 10.93 (br s, 1H). ¹³CNMR (400 MHz, DMSO-d₆) δ 11.07, 22.18, 71.41, 100.93, 105.64, 110.21,135.53, 145.16, 158.47, 161.10. MS 256 (MH⁺).

Example 158a: 2-Sulfamoylamino-6-propoxybenzonitrile

To a solution of 2-amino-6-propoxybenzonitrile (Example 158b) (4.23 g,24.01 mmol) in dimethylacetamide (20 mL) under N₂ was added sulfamoylchloride (5.56 g, 48.02 mmol). The reaction mixture was then stirred atroom temperature under nitrogen for 4 hours. Upon completion, thereaction was quenched by addition of ice/water (250 mL). The resultingprecipitate was collected by filtration, rinsed with water and dried toyield 2-sulfamoylamino-6-propoxybenzonitrile (4.73 g, 77%) as a paleyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.01 (d, J=7.2 Hz, 3H), 1.76(sext, J=7.2 Hz, 2H), 4.08 (t, J=6.8 Hz, 2H), 6.96 (d, J=8.5 Hz, 1H),7.15 (t, J=8.5 Hz, 1H), 7.28 (br s, 2H), 7.57 (d, J=8.5 Hz, 1H), 9.46(s, 1H). MS 256 (MH⁺).

Example 158b: 2-Amino-6-propoxybenzonitrile

2-Nitro-6-propoxybenzonitrile (Example 158c) (4.95 g, 24.01 mmol) wasdissolved in EtOH (50 mL) and THF (15 mL). 10% Pd/C (255 mg, 2.4 mmol)was added, and the reaction was hydrogenated using a Parr apparatus for12 hours at 40 psi. Upon completion, the reaction was filtered throughcelite and the filtrate concentrated to provide2-nitro-6-propoxybenzonitrile (4.3 g, 100%) as a light brown gel. ¹H NMR(400 MHz, CDCl₃) δ 1.05 (d, J=7.4 Hz, 3H), 1.83 (sext, J=7.0 Hz, 2H),3.96 (t, J=7.0 Hz, 2H), 4.38 (br s, 2H), 6.20 (d, J=8.5 Hz, 1H), 6.28(t, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H).

Example 158c: 2-Nitro-6-propoxybenzonitrile

To a solution of 2,6-dinitrobenzonitrile (6 g, 31.07 mmol) in dry DMF(45 mL) at 0° C., was added a solution of sodium (815 mg, 35.42 mmol) inn-propanol (23.5 mL) dropwise over 30 minutes. After compete addition,the reaction mixture was warmed to room temperature and stirred for 2.5hours. The reaction was poured into an ice/water mixture (250 mL), andthe precipitate was collected by filtration and dried to yield2-nitro-6-propoxybenzonitrile (4.95 g, 77%) as a light brown solid. ¹HNMR (400 MHz, CDCl₃) δ 1.11 (d, J=7.5 Hz, 3H), 1.93 (sext, J=7.5 Hz,2H), 4.14 (t, J=7.0 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H), 7.69 (t, J=8.6 Hz,1H), 7.82 (d, J=8.6 Hz, 1H).

Example 159:4-Amino-5,6-(5′,7′-dihydro-4′H-[2′,3′-c]pyrano)thieno[2,3-d]-pyrimidine-2(1H)-one

A solution ofN-(3-cyano-5,7-dihydro-4H-thieno[2,3-c]pyran-2-ylcarbamoyl) benzamide(Example 159a) (500 mg, 1.53 mmol) and NaOH (2 N, 2.1 mL) in EtOH (40mL) was stirred at 100° C. under nitrogen overnight. After cooling toroom temperature, the clear reaction solution was filtered, and thefiltrate was carefully neutralized with 10% AcOH with vigorous stirringat 0° C. The resultant precipitate was collected by filtration, washedwith water and then 20% EtOH in water to give the final product (280 mg,82%) as an off-white solid, which was dried under vacuum overnight.M.p.: >260° C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.83 (t, J=5.6 Hz, 2H), 3.86(t, J=5.6 Hz, 2H), 4.58 (s, 2H), 7.23 (brs, 2H), 11.56 (brs, 1H). MS 224(MH⁺).

Example 159a:N-(3-cyano-5,7-dihydro-4H-thieno[2,3-c]pyran-2-ylcarbamoyl) benzamide

To a solution of2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carbonitrile (Example 159b)(400 mg, 2.22 mmol) in 1.4-dioxane (30 mL) was added benzoyl isocyanate(327 mg, 2.22 mmol). The reaction mixture was then stirred at roomtemperature under nitrogen overnight. The precipitate was collected byfiltration, washed with 1.4-dioxane, and dried in the air to give thetitle compound (577 mg, 80%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.62 (t, J=5.2 Hz, 2H), 3.87 (t, J=5.2 Hz, 2H), 4.62 (s, 2H),7.56-7.53 (m, 2H), 7.67-7.65 (m, 1H), 8.04-8.01 (m, 2H), 11.60 (brs,1H), 12.13 (brs, 1H).

Example 159b: 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carbonitrile

To a mixture of dihydro-2H-pyran-4(3H)-one (820 mg, 8.19 mmol),malononitrile (541 mg, 8.19 mmol) and sulfur (263 mg, 8.19 mmol) inEthanol (50 mL) was added triethylamine (1.14 mL, 8.19 mmol). Thereaction mixture was then refluxed under nitrogen overnight. Aftercooling to room temperature, the precipitate was collected byfiltration, washed with ethanol, and dried in the air to give the titlecompound (1.15 g, 78%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆)δ 2.43-2.40 (m, 2H), 3.80 (t, J=5.6 Hz, 2H), 4.40 (t, J=2.0 Hz, 2H),7.09 (s, 2H). MS 181 (MH⁺).

Example 160:4-(2-(4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)ethyl)piperidiniumchloride

tert-Butyl-4-(2-(4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)ethyl)piperidine-1-carboxylate(Example 160a) (20 mg, 0.047 mmol) was dissolved in a solution of HCl inEtOH (1 mL, 1.25 M). The reaction was stirred at reflux under N₂. Uponcompletion, the precipitate was collected by vacuum filtration toprovide the desired product (17 mg, 100%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 1.38 (m, 2H), 1.73 (m, 1H), 1.81 (m, 2H), 1.87 (m, 2H),2.84 (m, 2H), 3.24 (m, 2H), 4.21 (t, J=6.4 Hz, 2H), 6.64 (d, J=8.1 Hz,1H), 6.78 (d, J=8.3 Hz, 1H), 7.47 (t, J=8.3 Hz, 1H), 7.81 (br s, 1H),8.35 (br s, 1H), 8.59 (m, 1H), 8.85 (m, 1H), 10.99 (br s, 1H). MS 325(MH⁺).

Example 160a: tert-Butyl4-(2-(4-amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)ethyl)piperidine-1-carboxylate

Prepared as in Example 158 from tert-butyl4-(2-(2-cyano-3-(sulfamoylamino)phenoxy)ethyl)piperidine-1-carboxylate(Example 160b) in 15% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.07 (qd, J=12.8, 4.6 Hz, 2H), 1.40 (s, 9H), 1.60 (m, 1H), 1.70 (m,2H), 1.79 (q, J=6.7 Hz, 2H), 2.70 (m, 2H), 3.93 (m, 2H), 4.21 (t, J=6.7Hz, 2H), 6.62 (d, J=8.1 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.3Hz, 1H), 7.82 (br s, 1H), 8.34 (br s, 1H), 10.96 (br s, 1H).

Example 160b: tert-Butyl-4-(2-(2-cyano-3-(sulfamoylamino)phenoxy) ethyl)piperidine-1-carboxylate

Prepared as in Example 158a from tert-butyl4-(2-(3-amino-2-cyanophenoxy)ethyl)piperidine-1-carboxylate (Example160c) in 72% yield as a clear syrup. ¹H NMR (400 MHz, DMSO-d₆) δ 1.08(m, 2H), 1.40 (s, 9H), 1.71 (m, 5H), 2.70 (m, 2H), 3.93 (m, 2H), 4.17(t, J=6.3 Hz, 2H), 6.98 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.28(br s, 2H), 7.57 (t, J=8.3 Hz, 1H), 9.45 (br s, 1H).

Example 160c: tert-Butyl4-(2-(3-amino-2-cyanophenoxy)ethyl)piperidine-1-carboxylate

Prepared as in Example 158b from tert-butyl4-(2-(2-cyano-3-nitrophenoxy)ethyl)piperidine-1-carboxylate (Example160d) in 36% as a white foam. ¹H NMR (400 MHz, CDCl₃) δ 1.06 (m, 2H),1.40 (s, 9H), 1.68 (m, 5H), 2.70 (m, 2H), 3.93 (m, 2H), 4.05 (t, J=6.0Hz, 2H), 5.98 (br s, 2H), 6.23 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.4 Hz,1H), 7.18 (t, J=8.2 Hz, 1H).

Example 160d:tert-Butyl-4-(2-(2-cyano-3-nitrophenoxy)ethyl)piperidine-1-carboxylate

To a suspension of tert-butyl-4-(2-hydroxyethyl)piperidine-1-carboxylate(769 μL, 3.50 mmol) and NaH (118 mg, 3.50 mmol, 60% dispersion inmineral oil) in dry DMF (5 mL) at 0° C., was added a solution of2,6-dinitrobenzonitrile (614 mg, 3.18 mmol) in dry DMF (4 mL). Thereaction was stirred under N₂, warming to rt. Upon completion, thereaction was quenched with H₂O (50 mL), and the precipitate wascollected by vacuum filtration to providetert-butyl-4-(2-(2-cyano-3-nitrophenoxy)ethyl)piperidine-1-carboxylate(955 mg, 80%) as a tan solid ¹H NMR (400 MHz, CDCl₃) δ 1.09 (m, 2H),1.40 (s, 9H), 1.73 (m, 5H), 2.70 (m, 2H), 3.94 (m, 2H), 4.32 (t, J=6.8Hz, 2H), 7.75 (m, 1H), 7.92 (m, 2H).

Example 161:4-(2-(4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)piperidiniumChloride

Prepared as in Example 166 of WO 2008/154221 from tert-butyl4-(2-(4-amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)piperidine-1-carboxylate(Example 161a) in 89% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.49 (m, 2H), 1.90 (d, J=13.1 Hz, 2H), 2.23 (m, 1H), 2.89 (q, J=11.6Hz, 2H), 3.30 (d, J=12.3 Hz, 2H), 4.09 (br s, J=6.6 Hz, 2H), 6.65 (d,J=8.2 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 7.48 (t, J=8.2 Hz, 1H), 7.74 (brs, 1H), 8.33 (br s, 1H), 8.69 (m, 1H), 8.92 (m, 1H), 11.01 (s, 1H). MS272 (MH⁺).

Example 161a: tert-Butyl4-(2-(4-amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)piperidine-1-carboxylate

Prepared as in Example 158 from tert-butyl4-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)piperidine-1-carboxylate(Example 161b) in 91% as a white solid. MS 355 (MH⁺—C(CH₃)₃).

Example 161b: tert-Butyl 4-((2-cyano-3-(sulfamoylamino) phenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 158a from tert-butyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example161c) in 56% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR(400 MHz, DMSO-d₆) δ 1.20 (m, 2H), 1.41 (s, 9H), 1.76 (d, J=13.2 Hz,2H), 1.97 (m, 2H), 4.00 (m, 4H), 6.96 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.3Hz, 1H), 7.28 (s, 2H), 7.57 (t, J=8.3 Hz, 1H), 9.47 (s, 1H).

Example 161c: tert-Butyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 158b from tert-butyl4-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example161d) in 74% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.18(qd, J=12.6, 3.8 Hz, 2H), 1.41 (s, 9H), 1.74 (d, J=12.6 Hz, 2H), 1.93(m, 2H), 2.75 (m, 2H), 3.88 (d, J=6.6 Hz, 2H), 3.99 (br d, J=12.1 Hz,2H), 6.00 (br s, 2H), 6.21 (d, J=8.2 Hz, 1H), 6.34 (d, J=8.3 Hz, 1H),7.18 (t, J=8.2 Hz, 1H).

Example 161d: tert-Butyl4-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 158c from 2,6-dinitrobenzonitrile and tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate in 73% as a tan solid. ¹H NMR(400 MHz, MeOD) δ 1.24 (qd, J=12.8, 4.4 Hz, 2H), 1.41 (s, 9H), 1.78 (brd, J=12.1 Hz, 2H), 2.02 (m, 2H), 2.77 (m, 2H), 4.00 (br d, J=13.1 Hz,2H), 4.15 (d, J=6.3 Hz, 2H), 7.74 (dd, J=7.5, 1.5 Hz, 1H), 7.91 (m, 2H).

Example 162:4-Amino-5-(tetrahydro-2H-pyran-4-yloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (Example162a) in 69% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.77(m, 2H), 2.05 (m, 2H), 3.51 (td, J=11.6, 2.1 Hz, 2H), 3.85 (dt, J=11.4,3.9 Hz, 2H), 4.83 (sept, J=4.1 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.88 (d,J=8.4 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.78 (br s, 1H), 8.39 (br s, 1H),10.96 (br s, 1H). MS 298 (MH⁺).

Example 162a:2-Sulfamoylamino-6-(tetrahydro-2H-pyran-4-yloxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (Example 162b) in58% as a light orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.64 (m, 2H),1.99 (m, 2H), 3.53 (ddd, J=11.6, 8.3, 3.1 Hz, 2H), 3.85 (m, 2H), 4.80(sept, J=4.0 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H),7.28 (br s, 2H), 7.56 (t, J=8.5 Hz, 1H), 9.47 (br s, 1H).

Example 162b: 2-Amino-6-(tetrahydro-2H-pyran-4-yloxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (Example 162c) in49% as an orange syrup. MS 219 (MH⁺).

Example 162c: 2-Nitro-6-(tetrahydro-2H-pyran-4-yloxy)benzonitrile

Prepared as in Example 166d of WO 2008/154221 from2,6-dinitrobenzonitrile and tetrahydro-2H-pyran-4-ol in 100% yield as atan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.69 (m, 2H), 2.03 (m, 2H), 3.56(m, 2H), 3.87 (m, 2H), 4.98 (sept, J=3.8 Hz, 1H), 7.90 (m, 3H).

Example 163:4-Amino-5-(tetrahydrofuran-3-yloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(tetrahydrofuran-3-yloxy)benzonitrile (Example 163a)in 33% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.07 (m, 1H),2.26 (m, 1H), 3.74 (td, J=8.4, 4.7 Hz, 1H), 3.84 (m, 2H), 3.95 (d,J=10.4 Hz, 1H), 5.23 (m, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.4 Hz,1H), 7.45 (t, J=8.1 Hz, 1H), 7.64 (br s, 1H), 8.33 (br s, 1H), 10.97 (brs, 1H). MS 284 (MH⁺).

Example 163a: 2-Sulfamoylamino-6-(tetrahydrofuran-3-yloxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(tetrahydrofuran-3-yloxy)benzonitrile (Example 163b) in 40%yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.99 (m, 1H),2.28 (m, 1H), 3.77 (td, J=8.3, 4.7 Hz, 1H), 3.83 (m, 1H), 3.87 (d, J=7.3Hz, 1H), 3.92 (dd, J=10.2, 4.4 Hz, 1H), 5.19 (m, 1H), 6.96 (d, J=8.3 Hz,1H), 7.18 (d, J=8.3 Hz, 1H), 7.29 (s, 2H), 7.58 (t, J=8.3 Hz, 1H), 9.49(br s, 1H).

Example 163b: 2-Amino-6-(tetrahydrofuran-3-yloxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-(tetrahydrofuran-3-yloxy)benzonitrile (Example 163c) in 97%yield as a light brown syrup. MS 205 (MH⁺).

Example 163c: 2-Nitro-6-(tetrahydrofuran-3-yloxy)benzonitrile

Prepared as in Example 166d of WO 2008/154221 from2,6-dinitrobenzonitrile and tetrahydrofuran-3-ol in 50% yield as a lightyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.04 (m, 1H), 2.32 (m, 1H),3.81 (td, J=8.3, 4.6 Hz, 1H), 3.89 (m, 2H), 3.98 (dd, J=10.8, 4.5 Hz,1H), 5.36 (m, 1H), 7.75 (dd, J=8.1, 1.5 Hz, 1H), 7.91 (t, J=8.2 Hz, 1H),7.95 (dd, J=8.2, 1.6 Hz, 1H).

Example 164:4-Amino-5-(1-isopropylpiperidin-4-yloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 111 of WO 2008/154221 from2-sulfamoylamino-6-(1-isopropylpiperidin-4-yloxy)benzonitrile (Example164a) in 12% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.24(d, J=6.7 Hz, 6H), 2.11 (m, 2H), 2.28 (m, 2H), 3.13 (m, 4H), 4.87 (m,1H), 6.67 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 7.49 (t, J=8.3 Hz,1H), 7.67 (br s, 1H), 8.43 (br s, 1H), 10.79 (br s, 1H). MS 339 (MH⁺).

Example 164a:2-Sulfamoylamino-6-(1-isopropylpiperidin-4-yloxy)benzonitrile

Prepared as in Example 111a of WO 2008/154221 from2-amino-6-(1-isopropylpiperidin-4-yloxy)benzonitrile (Example 164b). Theproduct was carried onto the next step without further purification.

Example 164b: 2-Amino-6-(1-isopropylpiperidin-4-yloxy)benzonitrile

Prepared as in Example 111b of WO 2008/154221 from2-nitro-6-(1-isopropylpiperidin-4-yloxy)benzonitrile (Example 164c) in80% yield as a brown syrup. MS 260 (MH⁺).

Example 164c: 2-Nitro-(1-isopropylpiperidin-4-yloxy)-6-benzonitrile

Prepared as in Example 166d of WO 2008/154221 from2,6-dinitrobenzonitrile and 1-isopropylpiperidin-4-ol in 90% yield as atan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.99 (d, J=6.8 Hz, 6H), 1.72 (m,2H), 1.95 (m, 2H), 2.41 (m, 2H), 2.71 (m, 3H), 4.80 (m, 1H), 7.81 (dd,J=8.2, 1.3 Hz, 1H), 7.89 (m, 2H).

Example 165:(R)-4-Amino-5-((1-butyrylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

To a solution of(R)-2-amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile (84 mg,0.29 mmol) (Example 165a) in acetonitrile (9 mL), was added sulfamoylchloride (70 mg, 0.60 mmol). The reaction was stirred at rt for 20 h,and upon completion was concentrated in vacuo. The resulting residue wasdissolved in EtOH (1 mL), and 2N aqueous NaOH (4 mL) was added. Themixture was refluxed for 2 h, and upon completion was cooled to rt,neutralized with 1N HCl and stirred at 0° C. The resulting precipitatewas collected by vacuum filtration to provide the desired product (38mg, 35%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.89 (t, J=7.3Hz, 3H), 1.54 (sext, J=7.3 Hz, 2H), 1.94 (m, 4H), 2.26 (t, J=7.3 Hz,2H), 3.49 (m, 2H), 4.10 (m, 1H), 4.25 (m, 1H), 4.43 (m, 1H), 6.62 (d,J=8.2 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 8.08 (brs, 1H), 8.34 (br s, 1H), 10.93 (br s, 1H). MS 367 (MH⁺).

Example 165a:(R)-2-Amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile

Prepared as in Example 111b of WO 2008/154221 from(R)-2-((1-butyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile (Example165b) in 77% yield. MS 274 (MH⁺).

Example 165b:(R)-2-((1-Butyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile

To a suspension of (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidiniumchloride (140 mg, 0.49 mmol) (Example 165c) in THF (3 mL) were addedEt₃N (143 μL, 1.03 mmol) and butyryl chloride (56 μL, 0.54 mmol). Thereaction was stirred for 72 h at rt under N₂. Upon completion, thereaction was filtered, and the filtrate was concentrated to provide(R)-2-((1-butyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile (127 mg,82%) as a yellow syrup. MS 318 (MH⁺).

Example 165c: (R)-2-((2-Cyano-3-nitrophenoxy)methyl)pyrrolidiniumChloride

Prepared as in Example 166 of WO 2008/154221 from (R)-tert-butyl2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate (Example165d) in 71% yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.92 (m, 2H), 2.14 (m, 2H), 3.28 (m, 2H), 4.07 (m, 2H), 4.50 (dd,J=710.6, 6.4 Hz, 1H), 4.57 (dd, J=10.9, 3.5 Hz, 1H), 7.77 (d, J=8.0 Hz,1H), 7.98 (m, 2H), 9.36 (br s, 1H), 9.74 (br s, 1H).

Example 165d: (R)-tert-Butyl2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 160d from 2,6-dinitrobenzonitrile and(R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 87% yieldas a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (s, 9H), 1.82 (m, 1H),2.02 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.32 (m, 2H), 7.79 (d, J=8.0Hz, 1H), 7.91 (m, 2H).

Example 161:(R)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-propylpyrrolidine-1-carboxamide

Prepared as in Example 165 from(R)-2-((3-amino-2-cyanophenoxy)methyl)-N-propylpyrrolidine-1-carboxamide(Example 166a) in 57% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 0.83 (t, J=7.6 Hz, 3H), 1.42 (sext, J=7.3 Hz, 2H), 1.90 (m, 4H), 3.00(m, 2H), 3.20 (m, 1H), 3.43 (m, 2H), 4.01 (m, 1H), 4.16 (m, 1H), 4.33(m, 1H), 6.27 (m, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H),7.45 (t, J=8.2 Hz, 1H), 8.19 (br s, 1H), 8.27 (br s, 1H), 10.91 (s, 1H).MS 382 (MH⁺).

Example 166a:(R)-2-((3-Amino-2-cyanophenoxy)methyl)-N-propylpyrrolidine-1-carboxamide

Prepared as in Example 158b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-propylpyrrolidine-1-carboxamide(Example 166b) in 14% yield. MS 303 (MH⁺).

Example 166b:(R)-2-((2-Cyano-3-nitrophenoxy)methyl)-N-propylpyrrolidine-1-carboxamide

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example165c) and propyl isocyanate in 100% yield as a light yellow solid. MS333 (MH⁺).

Example 162:(R)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-ethylpyrrolidine-1-carboxamide

Prepared as in Example 165 from(R)-2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpyrrolidine-1-carboxamide(Example 167a) in 60% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.02 (t, J=6.8 Hz, 3H), 1.90 (m, 4H), 3.08 (quint, J=6.8 Hz, 2H), 3.20(m, 2H), 4.01 (m, 1H), 4.16 (m, 1H), 4.33 (m, 1H), 6.27 (m, 1H), 6.62(d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 8.20(br s, 1H), 8.27 (br s, 1H), 10.91 (s, 1H). MS 368 (MH⁺).

Example 167a:(R)-2-((3-Amino-2-cyanophenoxy)methyl)-N-ethylpyrrolidine-1-carboxamide

Prepared as in Example 158b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-ethylpyrrolidine-1-carboxamide(Example 167b) in 62% yield. MS 289 (MH⁺).

Example 167b:(R)-2-((2-Cyano-3-nitrophenoxy)methyl)-N-ethylpyrrolidine-1-carboxamide

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example165c) and ethyl isocyanate in 95% yield as a light yellow solid. MS 319(MH⁺).

Example 163:(R)-4-Amino-5-((1-isobutyrylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 165 from(R)-2-amino-6-((1-isobutyrylpyrrolidin-2-yl)methoxy)benzonitrile(Example 168a) in 100% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.02 (d, J=6.3 Hz, 6H), 1.94 (m, 4H), 2.70 (m, 1H), 3.55 (m, 2H), 4.12(m, 1H), 4.24 (m, 1H), 4.43 (m, 1H), 6.62 (d, J=7.9 Hz, 1H), 6.91 (d,J=8.1 Hz, 1H), 7.47 (t, J=8.1 Hz, 1H), 8.04 (br s, 1H), 8.34 (br s, 1H),10.93 (br s, 1H). MS 367 (MH⁺).

Example 168a: (R)-2-Amino-6-((1-isobutyrylpyrrolidin-2-yl) methoxy)benzonitrile

Prepared as in Example 158b from(R)-2-((1-isobutyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile(Example 168b) in 80% yield as a clear syrup. MS 288 (MH⁺).

Example 168b:(R)-2-((1-Isobutyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride andisobutyryl chloride in 100% yield as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 0.96 (dd, J=6.6, 3.5 Hz, 6H), 1.93 (m, 4H), 2.14 (m, 1H),2.66 (sept, J=6.6 Hz, 1H), 3.55 (m, 1H), 4.28 (m, 3H), 7.79 (dd, J=7.6,1.8 Hz, 1H), 7.89 (m, 2H).

Example 164:(R)-4-Amino-5-((1-pivaloylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 176 of WO 2008/154221 from(R)-2-amino-6-((1-pivaloylpyrrolidin-2-yl)methoxy)benzonitrile (Example169a) in 64% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.18(s, 9H), 1.92 (m, 4H), 3.55 (m, 1H), 3.73 (m, 1H), 4.13 (m, 1H), 4.27(m, 1H), 4.48 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H),7.47 (t, J=8.2 Hz, 1H), 7.95 (br s, 1H), 8.37 (br s, 1H), 10.95 (br s,1H). MS 381 (MH⁺).

Example 169a:(R)-2-Amino-6-((1-pivaloylpyrrolidin-2-yl)methoxy)benzonitrile

Prepared as in Example 158b from(R)-2-((1-pivaloylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile (Example169b) in 91% yield as a clear syrup. MS 302 (MH⁺).

Example 169b:(R)-2-((1-Pivaloylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride andpivaloyl chloride in 99%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.16 (s, 9H), 1.91(m, 3H), 2.13 (m, 1H), 3.70 (m, 2H), 4.35 (m, 3H), 7.81 (dd, J=7.5, 2.1Hz, 1H), 7.92 (m, 2H).

Example 170:(R)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-isopropylpyrrolidine-1-carboxamide

Prepared as in Example 165 from(R)-2-((3-amino-2-cyanophenoxy)methyl)-N-isopropylpyrrolidine-1-carboxamide(Example 170a) in 23% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 1.05 (d, J=6.4 Hz, 6H), 1.87 (m, 4H), 3.17 (m, 1H), 3.79 (m,1H), 3.98 (m, 1H), 4.15 (m, 1H), 4.31 (m, 1H), 5.88 (d, J=7.4 Hz, 1H),6.59 (d, J=8.2 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 7.43 (t, J=8.2 Hz, 1H),8.18 (br s, 1H), 8.23 (br s, 1H), 10.88 (s, 1H). MS 382 (MH⁺).

Example 170a:(R)-2-((3-Amino-2-cyanophenoxy)methyl)-N-isopropylpyrrolidine-1-carboxamide

Prepared as in Example 158b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-isopropylpyrrolidine-1-carboxamide(Example 170b) in 86% yield as a clear syrup. 1H NMR (400 MHz, DMSO-d₆)δ 1.07 (d, J=5.9 Hz, 6H), 1.89 (m, 3H), 2.10 (m, 1H), 3.16 (m, 1H), 3.45(m, 1H), 3.78 (m, 1H), 3.91 (m, 1H), 4.06 (m, 1H), 4.12 (m, 1H), 5.85(d, J=7.7 Hz, 1H), 6.00 (br s, 2H), 6.31 (d, J=8.4 Hz, 1H), 6.34 (d,J=8.4 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H).

Example 170b:(R)-2-((2-Cyano-3-nitrophenoxy)methyl)-N-isopropylpyrrolidine-1-carboxamide

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example165c) and isopropyl isocyanate in 100% yield as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 1.07 (d, J=6.5 Hz, 6H), 1.91 (m, 3H), 2.13 (m, 1H),3.17 (m, 1H), 3.79 (m, 1H), 4.19 (m, 2H), 4.32 (d, J=8.8 Hz, 1H), 5.91(d, J=8.1 Hz, 1H), 7.89 (m, 3H).

Example 171:(R)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-tert-butylpyrrolidine-1-carboxamide

Prepared as in Example 165 from(R)-2-((3-amino-2-cyanophenoxy)methyl)-N-tert-butylpyrrolidine-1-carboxamide(Example 171a) in 56% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 1.27 (s, 9H), 1.89 (m, 4H), 3.21 (m, 1H), 4.02 (m, 1H), 4.19(m, 1H), 4.34 (m, 1H), 5.35 (s, 1H), 6.62 (m, 1H), 6.86 (m, 1H), 7.46(m, 1H), 8.23 (br s, 1H), 8.25 (br s, 1H), 10.91 (s, 1H). MS 396 (MH⁺).

Example 171a:(R)-2-((3-Amino-2-cyanophenoxy)methyl)-N-tert-butylpyrrolidin-1-carboxamide

Prepared as in Example 158b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-tert-butylpyrrolidine-1-carboxamide(Example 171b) in 96% yield as a white solid. MS 317 (MH⁺).

Example 171b:(R)-2-((2-Cyano-3-nitrophenoxy)methyl)-N-tert-butylpyrrolidine-1-carboxamide

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example176c) and tert-butyl isocyanate in 100% yield as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 1.s7 (s, 9H), 1.86 (m, 1H), 1.95 (m, 2H), 2.12(m, 1H), 3.18 (m, 1H), 3.37 (m, 1H), 4.20 (m, 1H), 4.23 (dd, J=16.0, 6.3Hz, 1H), 4.31 (dd, J=9.7, 2.7 Hz, 1H), 5.36 (s, 1H), 7.84 (dd, J=7.4,0.9 Hz, 1H), 7.91 (m, 2H).

Example 172:4-Amino-5-(methoxytetrahydro-2H-pyran-4-yl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(tetrahydro-2H-pyran-4-yl)benzonitrile (Example 172a)in 92% yield as a cream colored solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.31(m, 4H), 1.63 (br m, 4H), 3.31 (br m, 2H), 3.86 (br m, 2H), 4.01 (d,J=6.8 Hz, 2H), 6.57 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.41 (t,J=8.0 Hz, 1H), 7.68 (br, 1H), 8.24 (s, 1H), 10.90 (br, 1H). MS 312(MH⁺).

Example 172a: 2-Sulfamoylamino-6-(tetrahydro-2H-pyran-4-yl)benzonitrile

Prepared as in Example 158a from2-amino-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile (Example 172b)in 51% yield as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.35 (m,2H), 1.66 (br, 2H), 2.01 (br, 1H), 3.32 (br, 2H), 3.87 (br m, 2H), 3.96(d, J=6.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.19(br s, 2H), 7.52 (t, J=8.4 Hz, 1H), 9.44 (br s, 1H).

Example 172b: 2-Amino-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile (Example 172c)in 80% yield as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.32 (m,2H), 1.64 (m, 2H), 1.97 (br, 1H), 3.31 (m, 2H), 3.86 (m, 4H), 5.97 (s,2H), 6.19 (d, J=8.4 Hz, 1H), 6.31 (d, 1H), 7.15 (t, J=8.4 Hz, 1H).

Example 172c: 2-Nitro-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile

To a solution of tetrahydropyran-4-methanol (782 mg, 6.73 mmol) in THF(25 mL), was added slowly 1.38M nBuLi (4.13 mL, 5.70 mmol) in hexane at−78° C. under nitrogen. At one hour a solution of2,6-dinitrobenzonitrile (1.00 g, 5.18 mmol) in THF (25 mL) was added.The reaction was stirred under N₂ overnight at rt, then was quenchedwith water (100 mL). The precipitate was collected by filtration toprovide 2-nitro-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile (1.13g, 83%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.68 (m,2H), 2.06 (br, 1H), 3.33 (m, 2H), 3.88 (m, 2H), 4.11 (d, J=6.0 Hz, 2H),7.72 (d, J=6.0 Hz, 1H), 7.89-7.85 (m, 2H).

Example 173:4-Amino-5-(methoxytetrahydrofuran-3-yl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(methoxytetrahydrofuran-3-yl)benzonitrile (Example173a) in 26% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.64(m, 1H), 1.99 (m, 1H), 2.73 (m, 1H), 3.56 (m, 2H), 3.67 (m, 1H), 3.75(m, 1H), 4.04 (m, 2H), 6.51 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H),7.34 (t, J=8.0 Hz, 1H), 7.70 (br s, 1H), 8.09 (br s, 1H), 10.92 (br s,1H), MS 298 (M H+).

Example 173a:2-Sulfamoylamino-6-(methoxytetrahydrofuran-3-yl)benzonitrile

Prepared as in Example 158a from2-amino-6-((tetrahydrofuran-3-yl)methoxy)benzonitrile (Example 173b) in14% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.62 (m, 1H),1.96 (m, 1H), 2.43 (m, 1H), 2.61 (m, 1H), 3.48 (m, 1H), 3.60 (m, 1H),3.71 (m, 2H), 3.99 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.09 (d, J=8.0 Hz,1H), 7.19 (s, 1H), 7.49 (t, J=8.4 Hz, 1H), 9.42 (s, 1H).

Example 173b: 2-Amino-6-((tetrahydrofuran-3-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-((tetrahydrofuran-3-yl)methoxy)benzonitrile (Example 173c) in99% yield as a golden brown oil. MS 219 (MH⁺).

Example 173c: 2-Nitro-6-((tetrahydrofuran-3-yl)methoxy)benzonitrile

Prepared as in Example 160d from 2,6-dinitrobenzonitrile and3-hydroxymethyltetrahydrofuran in 48% yield as an orange-red solid. ¹HNMR (400 MHz, DMSO-d₆) δ 1.68 (m, 1H), 2.00 (m, 1H), 2.70 (m, 1H), 3.54(m, 1H), 3.66 (m, 1H), 3.76 (m, 2H), 4.03 (m, 1H), 4.19 (m, 1H), 7.73(d, J=7.6 Hz, 1H), 7.90-7.95 (m, 2H).

Example 174:4-Amino-5-((tetrahydrofuran-2-yl)methoxy)quinazolin-2(1H)-one

Prepared as in Example 158 fromN-(2-cyano-3-((tetrahydrofuran-2-yl)methoxy)phenylcarbamoyl)benzamide(Example 174a) in 39% yield. ¹H NMR (400 MHz, d-DMSO) δ 1.65 (br m, 1H),1.85 (br m, 2H), 1.99 (br m, 1H), 3.71 (m, 2H), 3.78 (m, 1H), 3.98 (m,1H), 6.70-6.67 (m, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.88 (s,1H), 10.62 (s, 1H).

Example 174a: N-(2-Cyano-3-((tetrahydrofuran-2-yl)methoxy) phenylcarbamoyl)benzamide

Prepared as in Example 159a from2-amino-6-((tetrahydrofuran-2-yl)methoxy)benzonitrile (Example 174b) in45% yield as a white solid. ¹H NMR (400 MHz, d-DMSO) δ 1.98-1.74 (m,4H), 3.54 (m, 1H), 3.69 (m, 1H), 4.20-4.07 (m, 3H), 6.97 (d, J=8.8 Hz,1H), 7.67-7.51 (m, 4H).

Example 174b: 2-Amino-6-((tetrahydrofuran-2-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-((tetrahydrofuran-2-yl)methoxy)benzonitrile (Example 174c) in92% yield as a light blue clear oil. ¹H NMR (400 MHz, MeOD) δ 1.97-1.68(m, 4H), 3.75-3.64 (m, 1H), 3.80-3.75 (m, 1H), 3.98-3.90 (m, 2H),4.15-4.12 (m, 1H), 5.96 (s, 1H), 6.18 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.0Hz, 1H), 7.14 (t, J=8.4 Hz, 1H).

Example 174c: 2-Nitro-6-((tetrahydrofuran-2-yl)methoxy)benzonitrile

Prepared as in Example 160d from 2,6-dinitrobenzonitrile andtetrafurfuryl alcohol in 68% yield. ¹H NMR (400 MHz, MeOD) δ 2.10-1.70(m, 7H), 3.68-3.66 (m, 1H), 3.80-3.78 (m, 1H), 4.29-4.20 (m, 3H), 7.72(d, J=6.0 Hz, 1H), 7.90-7.84 (m, 2H).

Example 175:4-Amino-5-(2-methoxybenzyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from 2-sulfamoylamino-6-(4-methoxybenzyloxy)benzonitrile (Example 175a) in 85% yield. ¹H NMR (400 MHz, DMSO-d₆) δ3.81 (s, 3H), 5.25 (s, 2H), 6.59 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.0 Hz,1H), 6.96 (t, J=7.2 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.37 (t, J=8.0 Hz,1H), 7.46-7.42 (m, 2H), 7.91 (s, 1H), 8.31 (s, 1H), 10.96 (s, 1H). MS334 (MH⁺).

Example 175a: 2-Sulfamoylamino-6-(2-methoxybenzyloxy) benzonitrile

Prepared as in Example 158a from2-amino-6-((tetrahydrofuran-2-yl)methoxy)benzonitrile (Example 175b) in23% yield. ¹H NMR (400 MHz, d-DMSO) δ 3.80 (s, 3H), 6.88 (d, J=8.4 Hz,1H), 6.88 (d, J=8.1 Hz 1H), 6.96 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz,2H), 7.16 (d, J=8.4 Hz, 1H), 7.39-7.33 (m, 5H), 7.45 (d, J=7.2 Hz, 1H),11.20 (s, 1H).

Example 175b: 2-Amino-6-(2-methoxybenzyloxy) benzonitrile

Prepared as in Example 158b from 2-nitro-6-(2-methoxybenzyloxy)benzonitrile (example 1750c) in 56% yield. ¹H NMR (400 MHz, MeOD) δ 3.79(s, 3H), 5.04 (s, 2H), 6.30-6.26 (m, 2H), 7.06-6.94 (m, 3H), 7.33-7.28(m, 3H), 7.54 (s, 1H).

Example 175c: 2-Nitro-6-(2-methoxybenzyloxy) benzonitrile

Prepared as in Example 158c from 2,6-dinitrobenzonitrile and2-methoxybenzyl alcohol in 58% yield. ¹H NMR (400 MHz, DMSO) δ 3.82 (s,3H), 5.34 (s, 2H), 6.99 (t, J=7.6 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.37(t, J=8.4 Hz, 1H), 7.46 (d, J=6.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H),7.93-7.87 (m, 2H).

Example 176:4-Amino-5-(methoxytetrahydrofuran-2-yl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(methoxytetrahydrofuran-2-yl)benzonitrile (Example176a) in 100% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.65(m, 1H), 1.86 (m, 1H), 1.98 (m, 1H), 3.69 (m, 1H), 3.78 (m, 1H), 3.98(m, 1H) 4.25 (m, 1H), 6.61 (d, J=7.2 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H).

Example 176a:2-Sulfamoylamino-6-(methoxytetrahydrofuran-2-yl)benzonitrile

Prepared as in Example 158a from2-amino-6-((tetrahydrofuran-2-yl)methoxy)benzonitrile (Example 39b) in79% yield as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.02-1.68(m, 2H), 3.66 (m, 1H), 3.81-3.76 (m, 1H), 4.20-4.03 (m, 3H), 6.93 (d,J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 7.53 (t, J=8.4 Hz,1H), 9.34 (br s, 1H).

Example 177:4-Amino-5-(furan-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(furan-3-ylmethoxy)benzonitrile (Example 177a) in 45%yield as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.11 (s, 2H),6.54 (d, J=0.4 Hz, 1H), 6.56 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.39 (t,J=8.4 Hz, 1H), 7.64 (s, 1H), 7.74 (s, 1H), 7.81 (s, 1H), 8.23 (s, 1H),10.90 (s, 1H). MS 294 (MH⁺).

Example 177a: 2-Sulfamoylamino-6-(furan-3-ylmethoxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(furan-3-ylmethoxy)benzonitrile (Example 177b) in 57% yield asan off white solid. ¹H NMR (400 MHz, d-DMSO) δ 5.04 (s, 2H), 6.62 (s,1H), 6.88 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.1, 0.8 Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 7.39-7.32 (m, 2H), 7.67 (s, 1H), 7.79 (s, 1H), 7.86 (s. 1H),7.93 (s, 1H), 10.91 (s, 1H).

Example 177b: 2-Amino-6-(furan-3-ylmethoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-(furan-3-ylmethoxy)benzonitrile (Example 177c) in 21% yield asa light yellow oil. ¹H NMR (400 MHz, d-DMSO) δ 4.92 (s, 2H), 6.31-6.26(m, 2H), 6.59 (s, 1H), 6.99 (t, J=8.4 Hz, 1H), 7.27 (s, 1H), 7.45 (s,1H), 7.66 (s, 1H), 7.76 (s, 1H).

Example 177c: 2-Nitro-6-(furan-3-ylmethoxy)benzonitrile

Prepared as in Example 158c from 2,6-dinitrobenzonitrile and3-furanmethanol in 100% yield. ¹H NMR (400 MHz, d-DMSO) δ 5.27 (s, 2H),6.59 (s, 1H), 7.69 (s, 1H), 7.91-7.84 (m, 4H).

Example 178:4-Amino-5-(3-methoxybenzyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(3-methoxybenzyloxy)benzonitrile (Example 178a) in54% yield. ¹H NMR (400 MHz, d-DMSO) δ 3.74 (s, 3H), 5.27 (s, 2H), 6.59(d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 7.04(d, J=7.2 Hz, 1H), 7.08 (s, 1H), 7.31 (t, J=8.4 Hz, 1H), 7.42 (t, J=8.0Hz, 1H), 7.89 (br s, 1H), 8.32 (br s, 1H), 10.96 (br s, 1H). MS 334(MH⁺).

Example 178a: 2-Sulfamoylamino-6-(3-methoxybenzyloxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(3-methoxybenzyloxy)benzonitrile (Example 178b) in 17% yieldas a white solid. MS 334 (MH⁺).

Example 178b: 2-Amino-6-(3-methoxybenzyloxy)benzonitrile

To a mixture of 2-nitro-6-(3-methoxybenzyloxy)benzonitrile (Example178c) (480 mg, 1.69 mmol) in 5:1 acetone:water (9 mL) was added zinc(552 mg, 8.44 mmol) and ammonium chloride (911 mg, 16.9 mmol). Thereaction was stirred at room temperature for 30 minutes, then filteredand concentrated. The residue was purified by flash chromatography(55:45 EtOAc:Hexane) to provide 2-amino-6-(benzyloxy)benzonitrile (337mg, 78%). ¹H NMR (400 MHz, d-DMSO) δ 3.73 (s, 3H), 5.04 (s, 1H), 6.27(d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 3H), 7.27 (t,J=8.0 Hz, 1H), 7.36 (s, 1H), 7.55 (s, 1H).

Example 178c: 2-(3-Methoxybenzyloxy)-6-nitrobenzonitrile

Prepared as in Example 158c from 2,6-dinitrobenzonitrile and3-methoxybenzylalcohol in 83% yield. ¹H NMR (400 MHz, d-DMSO) δ 3.75 (s,3H), 5.38 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.07(s, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 4H), 7.93-7.87 (m,2H).

Example 179:4-(2-(4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)pyrrolidiniumChloride

Prepared as in Example 160 from tert-Butyl3-(2-(4-amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)pyrrolidine-1-carboxylate(Example 179a) in 27% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.72 (m, 1H), 2.07 (m, 1H), 2.52 (m, 1H), 2.64 (m, 1H), 2.94-2.74 (m,3H), 3.79 (m, 2H), 6.26 (d, J=8.0 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 7.09(t, J=8.0 Hz, 1H), 7.31 (br s, 1H), 7.96 (br s, 1H), 9.03 (br s, 1H).

Example 179a: tert-Butyl3-(2-(4-amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 158 fromtert-butyl-3-((2-cyano-3-(sulfamoylmethyl)phenoxy)methyl)pyrrolidine-1-carboxylate (Example 179b) in 94% yield as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 1.37 (s, 9H), 1.66 (br m, 1H), 1.97 (br m,1H), 2.78 (br m, 1H), 3.48-3.20 (br m, 4H), 4.12 (br, m 2H), 6.60 (d,J=8.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.70 (s,1H), 8.33 (s, 1H), 10.95 (s, 1H).

Example 179b: tert-Butyl 3-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 158a from tert-butyl3-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example179c) in 47% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.37(s, 9H), 1.70 (br, 1H), 1.97 (br, 1H), 2.63 (br, 1H), 3.47-2.98 (br m,4H), 4.08 (br m, 2H), 6.94 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H),7.24 (s, 1H), 7.48 (s, 1H), 7.54 (t, J=8.0, 1H), 9.48 (br s, 1H).

Example 179c: tert-Butyl3-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-l-carboxylate

Prepared as in Example 158b fromtert-butyl-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate(Example 179d) in 100% yield as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ1.37 (s, 9H), 1.69 (br, 1H), 1.96 (br, 1H), 2.59 (br, 1H), 3.07 (br,1H), 3.23 (br, 1H), 3.35 (br, 1H), 3.40 (br, 1H), 3.96 (m, 2H), 5.98 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.4 Hz,1H).

Example 179d:tert-Butyl-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 160d from 2,6-dinitrobenzonitrile and tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate in 69% yield as a yellowsolid. MS 347 (MH⁺).

Example 180:(R)-4-Amino-5-((1-acetylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 165 from(R)-2-amino-6-((1-acetylpyrrolidin-2-yl)methoxy)benzonitrile (Example180a) in 31% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.90(m, 4H), 2.00 (s, 3H), 3.49 (m, 2H), 4.09 (dd, J=9.7, 6.1 Hz, 1H), 4.24(dd, J=9.8, 5.7 Hz, 1H), 4.41 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.87 (d,J=8.5 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 8.12 (br s, 1H), 8.33 (br s, 1H),10.93 (br s, 1H). MS 339 (MH⁺).

Example 180a:(R)-2-Amino-6-((1-acetylpyrrolidin-2-yl)methoxy)benzonitrile

Prepared as in Example 158b from(R)-2-((1-acetylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile (Example180b) in 77% yield as a clear syrup. MS 260 (MH⁺).

Example 180b:(R)-2-((1-Acetylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile

Prepared as in Example 165b from(R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and acetylchloride in 100% yield as a yellow syrup. MS 290 (MH⁺).

Example 181:4-Amino-5-(methoxy-3-pyrolidine-1-propionyl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-((1-propionylpyrrolidin-3-yl)methoxybenzonitrile(Example 181a) in 29% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 0.95 (t, J=7.6 Hz, 3H), 1.66 (m, 1H), 1.77 (m, 1H), 1.97 (m,1H), 2.05 (m, 1H), 2.21 (q, J=8.0 Hz, 2H), 2.74 (m, 1H), 2.86 (m, 1H),3.63-3.23 (m, 4H), 4.13 (m, 2H), 6.60 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.4Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.72 (s, 1H), 8.37-8.32 (m, 1H), 10.94(s, 1H).

Example 181a: 2-Sulfamoylamino-6-((1-propionylpyrrolidin-3-yl)methoxybenzonitrile

Prepared as in Example 158a from2-amino-6-((1-propionylpyrrolidin-3-yl)methoxy)benzonitrile (Example181b) in 27% yield as a white solid. MS 353 (MH⁺).

Example 181b:2-Amino-6-((1-propionylpyrrolidin-3-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-((1-propionylpyrrolidin-3-yl)methoxy)benzonitrile (Example181c) in 100% yield as a clear oil. MS 274 (MH⁺).

Example 181c:2-Nitro-6-((1-propionylpyrrolidin-3-yl)methoxy)benzonitrile

Prepared as in Example 165b from2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example181d) and propionyl chloride in 51% as a yellow solid. MS 304 (MH⁺).

Example 181d: 2-Nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrilehydrochloride

Prepared as in Example 160 fromtert-butyl-((2-cyano-3-nitorphenoxy)methyl)pyrrolidine-1-carboxylate(Example 44d) in 100% yield as a yellow solid. MS 248 (MH⁺).

Example 182:4-Amino-5-(methoxy-3-pyrolidine-1-butyryl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-((1-butyrylpyrrolidin-3-yl)methoxybenzonitrile(Example 182a) in 73% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 0.86 (t, J=7.6 Hz, 3H), 1.48 (q, J=7.6 Hz, 2H), 1.65 (m, 1H), 1.76 (m,1H), 1.97 (m, 1H), 2.05 (m, 1H), 2.17 (t, J=7.2 Hz, 2H), 2.74 (m, 1H),2.85 (m, 1H), 3.10 (m, 1H), 3.64-3.23 (m, 4H), 4.12 (m, 1H), 6.60 (d,J=8.0 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.71 (s,1H), 8.35-8.32 (m, 1H), 10.94 (s, 1H).

Example 182a:2-Sulfamoylamino-6-((1-butyrylpyrrolidin-3-yl)methoxybenzonitrile

Prepared as in Example 158a from2-amino-6-((1-butyrylpyrrolidin-3-yl)methoxy)benzonitrile (Example 182b)in 19% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.85 (t,J=7.6 Hz, 3H), 1.48 (q, J=7.6 Hz, 2H), 2.13-1.64 (m, 2H), 2.17 (m, 2H),2.75-2.53 (m, 2H), 3.65-3.18 (m, 4H), 4.09 (m, 2H), 6.94 (m, 1H), 7.13(m, 1H), 7.25 (s, 1H), 7.54 (m, 1H), 9.45 (m, 1H).

Example 182b: 2-Amino-6-((1-butyrylpyrrolidin-3-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-((1-butyrylpyrrolidin-3-yl)methoxy)benzonitrile (Example 182c)in 100% yield as a brown oil. MS 288 (MH⁺).

Example 182c: 2-Nitro-6-((1-butyrylpyrrolidin-3-yl)methoxy)benzonitrile

Prepared as in Example 165b from2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example181d) and butyryl chloride in 100% yield as an orange solid. MS 318(MH⁺).

Example 183:(E)-4-Amino-5-(1-(propylcarbamoyl)cyclopropylmethoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from1-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)-N-propylcyclopropanecarboxamide(Example 183a) in 94% yield as a white solid. ¹H-NMR (400 MHz, DMSO-d₆)δ10.95 (broad s, 1H), 8.35 (broad s, 1H), 7.95 (broad s, 1H), 7.76 (t,J=5.2 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.61 (d,J=7.6 Hz, 1H), 4.22 (s, 2H), 3.01 (q, J=6.4 Hz, 2H), 1.40 (hex, J=6.8Hz, 2H), 1.12-1.18 (m, 2H), 0.88-0.95 (m, 2H), 0.80 (t, J=7.6 Hz, 3H).MS 353 (MH⁺).

Example 183a:1-((2-Cyano-3-(sulfamoylamino)phenoxy)methyl)-N-propylcyclopropanecarboxamide

Prepared as in Example 158a from1-((3-amino-2-cyanophenoxy)methyl)-N-propylcyclopropanecarboxamide(Example 183b) and sulfamoyl chloride in 78% yield as a white solid.¹H-NMR (400 MHz, DMSO-d₆) δ9.45 (broad s, 1H), 7.51-7.61 (m, 2H), 7.26(broad s, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.24 (s,2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=7.6 Hz, 2H), 1.08-1.14 (m,2H), 0.83-0.88 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

Example 183b:1-((3-Amino-2-cyanophenoxy)methyl)-N-propylcyclopropanecarboxamide

A solution of 1-(hydroxymethyl)-N-propylcyclopropanecarboxamide (Example183c) (0.67 g, 4.25 mmol) in anhydrous THF (10 mL) was treated with NaH(0.17 g, 4.25 mmol, 60% suspension in mineral oil) at 0° C., under anitrogen atmosphere. The obtained mixture was stirred at 0° C. for 10min and at rt over 30 min. Then, a solution of2-amino-6-fluorobenzonitrile (0.53 g, 3.86 mmol) in THF (5.0 mL) wasadded and the obtained mixture was heated at reflux overnight. The coldmixture was quenched with saturated aqueous solution of NH₄Cl (20 mL)and extracted with EtOAc (3×50 mL). The combined extract was washed withbrine, dried over anhydrous MgSO₄, filtered and evaporated. The residuewas purified by chromatography on silica gel using gradienthexanes-hexanes/EtOAc (4:6), to give 0.75 g (71%) of the title compoundas a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ7.51 (t, J=6.0 Hz, 1H),7.17 (t, J=8.0 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H),5.97 (broad s, 2H), 4.13 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex,J=6.8 Hz, 2H), 1.05-1.11 (m, 2H), 0.78-0.86 (m, 5H).

Example 183c: 1-(Hydroxymethyl)-N-propylcyclopropanecarboxamide

To a solution of ethyl 1-(propylcarbamoyl)cyclopropanecarboxylate(Example 183d) (1.65 g, 8.27 mmol) in EtOH (70 mL) was added NaBH₄ (0.97g, 25.64 mmol) at rt. The obtained mixture was stirred at rt over 2days, quenched with 1.5M HCl and concentrated under reduced pressure.The concentrated mixture was extracted with EtOAc (4×70 mL), thecombined extract was washed with saturated NaHCO₃ and brine, and wasdried over MgSO₄. The filtrate was evaporated and the residue waspurified by chromatography on silica gel using the solvent gradienthexanes-hexanes/EtOAc (1:9), to furnish 1.14 g (88%) of the product as awhite solid. ¹H-NMR (400 MHz, DMSO-d₆) δ7.49 (broad s, 1H), 5.09 (broads, 1H), 3.49 (s, 2H), 3.05 (q, J=6.4 Hz, 2H), 1.41 (hex, J=7.6 Hz, 2H),0.86-0.91 (m, 2H), 0.83 (t, J=7.2 Hz, 3H), 0.55-0.60 (m, 2H).

Example 183d: Ethyl 1-(propylcarbamoyl)cyclopropanecarboxylate

To a solution of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (Wheeler,T. N.; Ray, J. A. Synthetic Communications 1988, 18(2), 141) (1.52 g,9.62 mmol) and n-propylamine (0.63 g, 10.58 mmol) in anhydrous DMF (65mL) at rt, were added NaHCO₃ (4.04 g, 48.11 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.21 g,11.54 mmol) and 1-hydroxybenzotriazole hydrate (1.77 g, 11.54 mmol)under a nitrogen atmosphere. After being stirred at rt overnight, themixture was partitioned between water (100 mL) and EtOAc (300 mL). Theorganic phase was separated, washed with water and brine, and was driedover anhydrous MgSO₄. The filtrate was evaporated to give 1.65 g (86%)of the crude product which was used in the next step withoutpurification. ¹H-NMR (400 MHz, DMSO-d₆) δ8.33 (broad s, 1H), 4.08 (q,J=6.8 Hz, 2H), 3.07 (q, J=6.4 Hz, 2H), 1.43 (hex, J=6.4 Hz, 2H), 1.31(s, 4H), 1.17 (t, J=6.4 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H).

Example 184:(E)-4-Amino-5-(4-methoxybut-2-enyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(4-methoxybut-2-enyloxy)benzonitrile (Example 184a)in 91% yield as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ10.94 (broads, 1H), 8.34 (broad s, 1H), 7.90 (broad s, 1H), 7.45 (t, J=8.4 Hz, 1H),6.75 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.88-6.02 (m, 2H),4.75-4.81 (m, 2H), 3.88-3.93 (m, 2H), 3.22 (s, 3H). MS 298 (MH⁺).

Example 184a: 2-Sulfamoylamino-6-(4-methoxybut-2-enyloxy)benzonitrile

Prepared as in Example 158a from(E)-2-amino-6-(4-methoxybut-2-enyloxy)benzonitrile (Example 184b) in 93%yield as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ9.46 (broad s, 1H),7.56 (t, J=8.4 Hz, 1H), 7.26 (broad s, 2H), 7.15 (d, J=8.0 Hz, 1H), 6.96(d, J=8.8 Hz, 1H), 5.84-6.00 (m, 2H), 4.68-4.76 (m, 2H), 3.89-3.95 (m,2H), 3.23 (s, 3H).

Example 184b: (E)-2-Amino-6-(4-methoxybut-2-enyloxy)benzonitrile

To a solution of (E)-2-(4-methoxybut-2-enyloxy)-6-nitrobenzonitrile(Example 184c) (0.25 g, 1.00 mmol) in a mixture of AcOH, EtOH and water(33 mL, 1:1:1) was added iron powder (0.56 g, 10.00 mmol) at rt. Theobtained mixture was stirred at rt for 20 min, then was heated to 50° C.for a further 15 min, and allowed to cool. The suspension wasconcentrated under reduced pressure; the residue was treated with water(50 mL) and extracted with EtOAc (4×50 mL). The combined extract waswashed with saturated aqueous NaHCO₃ and brine, and was dried overanhydrous MgSO₄. The filtrate was evaporated and the residue waspurified by silica gel flash chromatography using gradienthexanes-hexanes/EtOAc (1:1), to give 0.19 g (86%) of the title compoundas a white solid. ¹H-NMR (400 MHz, DMSO-d₆) 7.17 (t, J=8.4 Hz, 1H), 6.34(d, J=8.8 Hz, 1H), 6.22 (d, J=8.4 Hz, 1H), 6.00 (broad s, 2H), 5.82-5.96(m, 2H), 4.56-4.62 (m, 2H), 3.88-3.93 (m, 2H), 3.23 (s, 3H).

Example 184c: (E)-2-(4-Methoxybut-2-enyloxy)-6-nitrobenzonitrile

To a solution of (E)-2-(4-hydroxybut-2-enyloxy)-6-nitrobenzonitrile(Example 184d) (0.50 g, 2.13 mmol) and2,6-di-tert-butyl-4-methylpyridine (2.18 g, 10.65 mmol) in CH₂Cl₂ (15.0mL) at rt, was added trimethyloxonium tetrafluoroborate (1.58 g, 10.65mmol) under a nitrogen atmosphere. After 1 h at rt, the reaction wasquenched with water (50 mL) and extracted with EtOAc (4×50 mL). Thecombined extract was washed with water, 1.5M HCl, saturated aqueousNaHCO₃ and brine, and was dried over anhydrous MgSO₄. The filtrate wasevaporated and the residue was purified by chromatography on silica gelusing the solvent gradient hexanes→hexanes/EtOAc (3:7), to give 0.25 g(72%) of the title compound as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆)δ7.84-7.92 (m, 2H), 7.68-7.73 (m, 1H), 5.82-6.03 (m, 2H), 4.82-4.88 (m,2H), 3.87-3.93 (m, 2H), 3.21 (s, 3H).

Example 184d: (E)-2-(4-Hydroxybut-2-enyloxy)-6-nitrobenzonitrile

Prepared as in Example 160d from (E)-but-2-ene-1,4-diol (Miller, A. E.G.; Biss, J. W.; Schwartzman, L. H. J. Org. Chem. 1959, 24, 627 in 30%yield as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ7.83-7.94 (m, 2H),7.67-7.74 (m, 1H), 5.97-6.07 (m, 1H), 5.78-5.89 (m, 1H), 4.80-89 (m,3H), 3.94-4.02 (m, 2H).

Example 185:4-Amino-5-(4,5-dihydrofuran-2-yl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(4,5-dihydrofuran-2-yl)benzonitrile (Example 185a) in31% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.75-2.81 (m,2H), 4.43 (t, J=9.2 Hz, 2H), 5.35-5.36 (m, 1H), 7.07 (dd, J=1.2, 8.0 Hz,1H), 7.12 (dd, J=1.2, 7.2 Hz, 1H), 7.50-7.54 (m, 1H), 8.2-8.4 (broad s,1H), 11.09 (s, 1H). MS 266 (MH⁺).

Example 185a: 2-Sulfamoylamino-6-(4,5-dihydrofuran-2-yl)benzonitrile

Prepared as in Example 158a from2-amino-6-(4,5-dihydrofuran-2-yl)benzonitrile (Example 185b) in 19%yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.82-2.88 (m, 2H),4.45 (t, J=9.6 Hz, 2H), 5.89 (t, J=3.2 Hz, 1H), 7.29 (s, 2H), 7.47 (d,J=7.2 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 9.42 (s,1H). MS 266 (MH⁺).

Example 185b: 2-amino-6-(4,5-dihydrofuran-2-yl)benzonitrile

2-Amino-6-bromobenzonitrile (0.75 g, 3.81 mmol),(4,5-dihydrofuran-2-yl)trimethylstannane (Menez, P.; Fargeas, V.;Poisson, J.; Ardisson, J.; Lallemand, J.-Y.; Pancrazi, A. TetrahedronLetters 1994, 35(42), 7767) (1.02 g, 4.38 mmol), and palladiumtetrakis(triphenylphosphine) (0.33 g, 0.28 mmol) were refluxed intoluene (10.0 mL) under nitrogen for 1.5 h. Saturated ammonium chloride(12 mL) and ammonium hydroxide (4 mL) were added, and the mixture wasextracted with EtOAc. The organic layer was concentrated under vacuumand the residue was purified by chromatography on silica using 35%EtOAc/hexanes to give 0.48 g (68%) of the title compound as yellow oil.¹H NMR (400 MHz, Acetone-d₆) δ 2.78-2.83 (m, 2H), 4.40 (t, J=9.2 Hz,2H), 5.76 (t, J=3.2 Hz, 1H), 6.04 (s, 2H), 6.77-6.80 (m, 2H), 7.28 (t,J=8.0 Hz, 1H). MS 187 (MH⁺).

Example 186:4-Amino-5-(tetrahydrofuran-2-yl)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(tetrahydrofuran-2-yl)benzonitrile (Example 186a) in52% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.94-2.05 (m,3H), 2.21-2.28 (m, 1H), 3.81-3.87 (m, 1H), 3.92-3.97 (m, 1H), 5.23-5.27(m, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.6Hz, 1H), 7.9-8.5 (broad, 2H), 10.94 (s, 1H). MS 268 (MH⁺).

Example 186a: 2-Sulfamoylamino-6-(tetrahydrofuran-2-yl)benzonitrile

2-Amino-6-(4,5-dihydrofuran-2-yl)benzonitrile (Example 186b) (0.24 g,1.28 mmol), 10% Pd/C (0.24 g), and ammonium formate (2.40 g, 38.1 mmol)were refluxed in MeOH (25 mL) under nitrogen for 1.5 h. The insolublesolids were filtered out and discarded, and the solvent was removedunder vacuum. The resultant residue was dissolved in EtOAc, washed withsaturated Na₂CO₃ and brine, dried over MgSO₄ and concentrated undervacuum. The residue was dissolved in anhydrous DMA (2.0 mL) and wastreated with sulfamoyl chloride (0.11 g, 0.97 mmol). The reactionmixture was stirred under nitrogen for 30 minutes, quenched with water(5.0 mL) and extracted with EtOAc (3×50 mL). The combined extract wasdried over MgSO₄, filtered and concentrated under vacuum. The crudeproduct was purified by silica gel prep-TLC using 65% EtOAc/hexanes togive 45.0 mg (13%) of the title compound as a white solid. ¹H NMR (400MHz, Acetone-d₆) δ 1.71-1.78 (m, 1H), 2.02-2.07 (m, 2H), 2.45-2.52 (m,1H), 3.90-3.95 (m, 1H), 4.10-4.15 (m, 1H), 5.08 (t, J=6.8 Hz, 1H),6.6-6.8 (broad, 2H), 7.36-7.39 (m, 1H), 7.62-7.63 (m, 2H), 8.22 (broads, 1H). MS 268 (MH⁺).

Example 187:4-Amino-5-(3-(pyridin-2-yl)propoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(3-(pyridin-2-yl)propoxy)benzonitrile (Example 187a)in 58% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.37 (quint,J=6.8 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 4.19 (t, J=6.0 Hz, 2H), 6.60 (d,J=8.4 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 7.19-7.22 (m, 1H), 7.29 (d, J=8.0Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.68-7.72 (m, 1H), 7.92 (s, 1H), 8.36(s, 1H), 8.49 (d, J=4.0 Hz, 1H), 10.94 (broad s, 1H). MS 333 (MH⁺).

Example 187a: 2-Sulfamoylamino-6-(3-(pyridin-2-yl)propoxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(3-(pyridin-2-yl)propoxy)benzonitrile (Example 187b) in 97%yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.15 (quint, J=6.4Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H), 6.93 (d, J=8.4Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.20-7.29 (m, 4H), 7.55 (t, J=8.4 Hz,1H), 7.68-7.72 (m, 1H), 8.48 (d, J=4.8 Hz, 1H), 9.49 (broad s, 1H). MS333 (MH⁺).

Example 187b: 2-Amino-6-(3-(pyridin-2-yl)propoxy)benzonitrile

Prepared as in Example 49b from2-nitro-6-(3-(pyridin-2-yl)propoxy)benzonitrile (Example 187c) in 85%yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.12 (quint, J=6.8Hz, 2H), 2.90 (t, J=7.2 Hz, 2H), 4.02 (t, J=6.4 Hz, 2H), 5.99 (s, 2H),6.18 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 7.14-7.22 (m, 2H), 7.26(d, J=8.0 Hz, 1H), 7.67-7.71 (m, 1H), 8.49 (d, J=3.6 Hz, 1H). MS 254(MH⁺).

Example 187c: 2-Nitro-6-(3-(pyridin-2-yl)propoxy)benzonitrile

Prepared as in Example 37c from 3-(pyridin-2-yl)propan-1-ol2,6-dinitrobenzonitrile in 86% yield as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.21 (quint, J=6.4 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 4.31 (t,J=6.4 Hz, 2H), 7.19-7.22 (m, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.67-7.74 (m,2H), 7.86-7.92 (m, 2H), 8.48 (d, J=4.8 Hz, 1H). MS 284 (MH⁺).

Example 188:4-Amino-5-(2-(pyridin-2-yl)ethoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(2-(pyridin-2-yl)ethoxy)benzonitrile (Example 188a)in 22% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.29 (t,J=5.6 Hz, 2H), 4.46 (t, J=5.6 Hz, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.75 (d,J=8.8 Hz, 1H), 7.28-7.31 (m, 1H), 7.40-7.46 (m, 2H), 7.75-7.80 (m, 1H),8.33-8.52 (m, 3H), 10.91 (s, 1H). MS 319 (MH⁺).

Example 188a: 2-Sulfamoylamino-6-(2-(pyridin-2-yl)ethoxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(2-(pyridin-2-yl)ethoxy)benzonitrile (Example 188b) in 67%yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.22 (t, J=6.4 Hz,2H), 4.48 (t, J=6.4 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.4 Hz,1H), 7.23-7.26 (m, 3H), 7.39 (d, J=7.6 Hz, 1H), 7.55 (t, J=8.4 Hz, 1H),7.73 (t, J=7.2 Hz, 1H), 8.51 (d, J=4.4 Hz, 1H), 9.42 (s, 1H). MS 319(MH⁺).

Example 188b: 2-Amino-6-(2-(pyridin-2-yl)ethoxy)benzonitrile

Prepared as in Example 197b from2-nitro-6-(2-(pyridin-2-yl)propoxy)benzonitrile (Example 188c) in 60%yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.18 (t, J=6.8 Hz,2H), 4.36 (t, J=6.8 Hz, 2H), 5.97 (s, 2H), 6.25 (d, J=8.4 Hz, 1H), 6.32(d, J=8.4 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.22-7.26 (m, 1H), 7.37 (d,J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 8.51 (d, J=4.4 Hz, 1H). MS 240 (MH⁺).

Example 188c: 2-Nitro-6-(2-(pyridin-2-yl)ethoxy)benzonitrile

Prepared as in Example 172c from 2-(pyridin-2-yl)ethanol and2,6-dinitrobenzonitrile in 82% yield as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 3.27 (t, J=6.4 Hz, 2H), 4.64 (t, J=6.4 Hz, 2H), 7.23-7.27 (m,1H), 7.41 (d, J=8.0 Hz, 1H), 7.71-7.79 (m, 2H), 7.86-7.91 (m, 2H),8.50-8.52 (m, 1H). MS 270 (MH⁺).

Example 189:4-Amino-5-((5-methylisoxazol-3-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-((5-methylisoxazol-3-yl)methoxy)benzonitrile (Example189a) in 83% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.42(s, 3H), 5.40 (s, 2H), 6.36 (s, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.81 (d,J=8.4 Hz, 1H), 7.48 (t, J=8.4 Hz, 1H), 8.06 (s, 1H), 8.40 (s, 1H), 11.02(s, 1H). MS 309 (MH⁺).

Example 189a:2-Sulfamoylamino-6-((5-methylisoxazol-3-yl)methoxy)benzonitrile

Prepared as in Example 158a from2-amino-6-((5-methylisoxazol-3-yl)methoxy)benzonitrile (Example 189b) in85% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.42 (s, 3H),5.32 (s, 2H), 6.34 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz,1H), 7.30 (s, 2H), 7.59 (t, J=8.8 Hz, 1H), 9.53 (s, 1H). MS 309 (MH⁺).

Example 189b: 2-Amino-6-((5-methylisoxazol-3-yl)methoxy)benzonitrile

Prepared as in Example 184184b from2-((5-methylisoxazol-3-yl)methoxy)-6-nitrobenzonitrile (Example 189c) in52% yield as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.42 (s, 3H),5.19 (s, 2H), 6.07 (s, 2H), 6.31-6.33 (m, 2H), 6.37 (d, J=8.4 Hz, 1H),7.20 (t, J=8.4 Hz, 1H). MS 230 (MH⁺).

Example 189c: 2-((5-Methylisoxazol-3-yl)methoxy)-6-nitrobenzonitrile

Prepared as in Example 172172c from (5-methylisoxazol-3-yl)methanol and2,6-dinitrobenzonitrile in 86% yield as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.43 (d, J=0.8 Hz, 3H), 5.50 (s, 2H), 6.38 (d, J=0.4 Hz, 1H),7.83 (dd, J=1.2, 8.4 Hz, 1H), 7.91-7.98 (m, 2H). MS 260 (MH⁺).

Example 190:(E)-4-Amino-5-(4-oxo-4-(propylamino)but-2-enyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from(E)-4-(2-cyano-3-(sulfamoylamino)phenoxy)-N-propylbut-2-enamide (Example190a) in 19% yield as a white solid. ¹H NMR (400 MHz, Acetone-d₆) δ 0.87(t, J=7.2 Hz, 3H), 1.47 (hex, J=7.6 Hz, 2H), 3.11-3.17 (m, 4H), 5.35 (q,J=7.2 Hz, 1H), 6.70 (d, J=6.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.87 (d,J=8.0 Hz, 1H), 7.2-7.5 (broad s, 2H), 7.51 (t, J=8.0 Hz, 1H), 8.19(broad s, 1H), 9.5-10.5 (broad s, 1H). MS 339 (MH⁺).

Example 190a:(E)-4-(2-Cyano-3-(sulfamoylamino)phenoxy)-N-propylbut-2-enamide

Prepared as in Example 158a from(E)-4-(3-amino-2-cyanophenoxy)-N-propylbut-2-enamide (Example 190b) in87% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.84 (t, J=7.2Hz, 3H), 1.43 (hex, J=6.8 Hz, 2H), 3.06 (q, J=6.8 Hz, 2H), 4.90 (d,J=2.8 Hz, 2H), 6.15 (d, J=15.6 Hz, 1H), 6.70-6.77 (m, 1H), 6.91 (d, J8.8 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.27 (broad s, 2H), 7.57 (t, J=8.8Hz, 1H), 8.13-8.16 (m, 1H), 9.52 (broad s, 1H). MS 339 (MH⁺).

Example 190b: (E)-4-(3-Amino-2-cyanophenoxy)-N-propylbut-2-enamide

Prepared as in Example 184b from(E)-4-(2-cyano-3-nitrophenoxy)-N-propylbut-2-enamide (Example 190c) in73% yield as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.84 (t, J=7.2Hz, 3H), 1.42 (hex, J=7.2 Hz, 2H), 3.06 (q, J=6.8 Hz, 2H), 4.77-4.79 (m,2H), 6.04 (s, 2H), 6.11-6.20 (m, 2H), 6.35 (d, J=8.4 Hz, 1H), 6.67-6.74(m, 1H), 7.18 (t, J=8.0 Hz, 1H), 8.11-8.14 (m, 1H). MS 260 (MH⁺).

Example 190c: (E)-4-(2-Cyano-3-nitrophenoxy)-N-propylbut-2-enamide

(E)-4-Bromo-N-propylbut-2-enamide (Elliott, M.; Farnham, A. W.; Janes,N. F.; Johnson, D. M.; Pulman, D. A. Pesticide Science 1987 18(4) 229)(0.14 g, 0.70 mmol), 2-hydroxy-6-nitrobenzonitrile (0.14 g, 0.88 mmol),potassium carbonate (0.39 g, 2.81 mmol), and 18-crown-6 (0.11 g, 0.42mmol) were refluxed in acetone (6 mL) for 2 h, and then poured into icewater (45 mL). The resultant precipitate was collected by filtration togive 0.16 g (79%) of the title compound as an off white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 0.84 (t, J=7.2 Hz, 3H), 1.42 (hex, J=7.2 Hz, 2H),3.06 (q, J=6.8 Hz, 2H), 5.07 (d, J=2.8 Hz, 2H), 6.16 (d, J=16.0 Hz, 1H),6.71-6.78 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.88-7.96 (m, 2H), 8.11-8.14(m, 1H).

Example 191:(S)-4-Amino-5-((1-acetylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 165 from(S)-2-amino-6-((1-acetylpyrrolidin-2-yl)methoxy)benzonitrile (Example191a) in 10% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.93(m, 4H), 2.00 (s, 3H), 3.50 (m, 2H), 4.09 (dd, J=10.0, 6.2 Hz, 1H), 4.24(dd, J=10.0, 5.6 Hz, 1H), 4.41 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.87 (d,J=8.5 Hz, 1H), 7.46 (t, J=8.5 Hz, 1H), 8.12 (br s, 1H), 8.33 (br s, 1H),10.93 (br s, 1H). MS 339 (MH⁺).

Example 191a:(S)-2-Amino-6-((1-acetylpyrrolidin-2-yl)methoxy)benzonitrile

To a suspension of (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidiniumchloride (130 mg, 0.46 mmol) (Example 191b) in THF (5 mL) were addedEt₃N (135 μL, 0.97 mmol) and acetyl chloride (36 μL, 0.50 mmol). Thereaction was stirred at rt for 18 h, filtered and diluted with EtOH (20mL). The resulting solution was hydrogenated (20 Bar) using 10% Pd/C asthe catalyst. Upon completion, the reaction mixture was concentrated toprovide the title compound (61 mg, 51%) as a clear syrup. MS 260 (MH⁺).

Example 191b: (S)-2-((2-Cyano-3-nitrophenoxy)methyl)pyrrolidiniumChloride

Prepared as in Example 160 from(S)-tert-butyl-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate(Example 191c) in 81% yield as an off-white solid. MS 248 (MH⁺—HCl).

Example 191c: (S)-tert-Butyl2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 160d from 2,6-dinitrobenzonitrile and(S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 89% yieldas a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.40 (s, 9H), 1.81 (m, 1H),2.03 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.33 (m, 2H), 7.79 (d, J=7.8Hz, 1H), 7.93 (m, 2H).

Example 192:(S)-4-Amino-5-((1-propionylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 165 from(S)-2-amino-6-((1-propionylpyrrolidin-2-yl)methoxy)benzonitrile (Example192a) in 17% yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.01 (t, J=7.8 Hz, 3H), 1.95 (m, 4H), 2.31 (m, 2H), 3.48 (m, 2H), 4.11(dd, J=10.0, 6.4 Hz, 1H), 4.27 (dd, J=9.8, 5.0 Hz, 1H), 4.43 (m, 1H),6.64 (d, J=7.9 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 7.48 (t, J=8.2 Hz, 1H),8.09 (br s, 1H), 8.34 (br s, 1H), 10.95 (br s, 1H). MS 353 (MH⁺).

Example 192a:(S)-2-Amino-6-((1-propionylpyrrolidin-2-yl)methoxy)benzonitrile

Prepared as in Example 191a from(S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example191b) and propionyl chloride in 90% yield as a clear syrup. MS 274(MH⁺).

Example 193:(S)-4-Amino-5-((1-butyrylpyrrolidin-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 165 from(S)-2-amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile (Example193a) in 78% yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ0.88 (t, J=7.5 Hz, 3H), 1.54 (q, J=7.5 Hz), 1.94 (m, 4H), 2.26 (t, J=7.5Hz, 2H), 3.48 (m, 2H), 4.10 (m, 1H), 4.25 (m, 1H), 4.43 (m, 1H), 6.62(d, J=8.1 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 7.47 (t, J=8.3 Hz, 1H), 8.08(br s, 1H), 8.32 (br s, 1H), 10.93 (br s, 1H). MS 367 (MH⁺).

Example 193a:(S)-2-Amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile

Prepared as in Example 191a from(S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example191b) and butyryl chloride to in 90% yield as a white solid. MS 288(MH⁺).

Example 194:(S)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-methylpyrrolidine-1-carboxamide

Prepared as in Example 165 from(S)-2-((3-amino-2-cyanophenoxy)methyl)-N-methylpyrrolidine-1-carboxamide(Example 194a) in 30% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 1.89 (m, 4H), 2.60 (d, J=3.9 Hz, 3H), 3.20 (m, 2H), 4.01 (m,1H), 4.16 (m, 1H), 4.32 (m, 1H), 6.23 (m, 1H), 6.62 (d, J=8.2 Hz, 1H),6.89 (d, J=8.5 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 8.19 (br s, 1H), 8.27(br s, 1H), 10.92 (s, 1H). MS 354 (MH⁺).

Example 194a:(S)-2-((3-Amino-2-cyanophenoxy)methyl)-N-methylpyrrolidine-1-carboxamide

Prepared as in Example 191a from(S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example191b) and methyl isocyanate in 53% yield as a white solid. MS 275 (MH⁺).

Example 195:(S)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-ethylpyrrolidine-1-carboxamide

Prepared as in Example 237 from(S)-2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpyrrolidine-1-carboxamide(Example 195a) in 68% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 1.03 (t, J=6.9 Hz, 6H), 1.90 (m, 4H), 3.08 (quint, J=6.6 Hz,2H), 3.20 (m, 1H), 3.31 (m, 1H), 4.00 (dd, J=9.7, 6.7 Hz, 1H), 4.17 (dd,J=9.7, 6.0 Hz, 1H), 4.33 (m, 1H), 6.27 (d, J=5.7 Hz, 1H), 6.62 (d, J=8.2Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 8.20 (br s,1H), 8.26 (br s, 1H), 10.91 (s, 1H). MS 368 (MH⁺).

Example 195a:(S)-2-((3-Amino-2-cyanophenoxy)methyl)-N-ethylpyrrolidine-1-carboxamide

Prepared as in Example 191a from(S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example191b) and ethyl isocyanate in 100% yield as a white solid. MS 289 (MH⁺).

Example 196:(S)-2-((4-Amino-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide-5-yloxy)methyl)-N-propylpyrrolidine-1-carboxamide

Prepared as in Example 237 from(S)-2-((3-amino-2-cyanophenoxy)methyl)-N-propylpyrrolidine-1-carboxamide(Example 196a) in 37% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 0.84 (t, J=7.6 Hz, 6H), 1.43 (sext, J=7.4 Hz, 2H), 1.92 (m,4H), 3.01 (m, 2H), 3.21 (m, 1H), 3.33 (m, 1H), 4.02 (dd, J=9.7, 6.4 Hz,1H), 4.18 (dd, J=9.7, 5.9 Hz, 1H), 4.34 (m, 1H), 6.27 (d, J=5.6 Hz, 1H),6.62 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H),8.20 (br s, 1H), 8.27 (br s, 1H), 10.91 (s, 1H). MS 382 (MH⁺).

Example 196a:(S)-2-((3-Amino-2-cyanophenoxy)methyl)-N-propylpyrrolidine-1-carboxamide

Prepared as in Example 191a from(S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example191b) and propyl isocyanate in 100% yield as a white solid. MS 303(MH⁺).

Example 197:3-(4-Amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2′,2′-dimethyl-N-propylpropanamide

To a stirred solution of3-(3-sulfamoylamino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide(18.52 g, 52.55 mmol) (Example 197a) in EtOH (150 mL) was added NaOHsolution (2.0 N, 52.3 mL) at room temperature. The reaction mixture wasthen refluxed for 2 hrs until the reaction was complete by TLC. Thesolution was cooled to 0° C. and neutralized carefully with 10% aceticacid and the precipitate was collected by filtration and washed withwater. The product was further purified by recrystallization fromEtOH/H₂O (1:4), dried under vacuum to give the title compound as a whitesolid (13.5 g, 73%). M.p.: 225-226° C. ¹H NMR (400 MHz, DMSO-d₆) δ 0.75(t, J=7.4 Hz, 3H), 1.22 (s, 6H), 1.38 (m, 2H), 3.01 (q, J=6.5 Hz, 2H),4.07 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.44 (t,J=8.0 Hz, 1H), 7.82 (t, J=5.6 Hz, 1H), 7.92 (s, 1H), 8.33 (s, 1H), 10.93(s, 1H). MS 355 (MH⁺).

Example 197a:3-(3-sulfamoylamino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide

To a solution of3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide (16.5 g,59.92 mmol) (Example 197b) in DMA (50 mL) was added sulfamoyl chloride(13.85 g, 119.84 mmol) at 0° C. under nitrogen. The reaction mixture wasthen stirred at room temperature under nitrogen for 3 hrs then dilutedwith EtOAc, washed successively with NaHCO₃, brine, dried over Na₂SO₄,filtered and evaporated to give the title compound as a off white solid(18.52 g, 87%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.79 (t, J=7.6 Hz, 3H), 1.20(s, 6H), 1.38 (m, 2H), 3.01 (q, J=6.5 Hz, 2H), 4.05 (s, 2H), 6.92 (d,J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.24 (s, 2H), 7.53 (t, J=8.4 Hz,1H), 7.55 (t, J=5.6 Hz, 1H), 9.42 (s, 1H). MS 355 (MH⁺).

Example 197b:3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide

Method A:

To a solution of3-(2-cyano-3-nitrophenoxy)-2,2-dimethyl-N-propylpropanamide (305 mg, 1.0mmol) (Example 197c) in EtOAc (20.0 mL) was added 10% Pd/C (50 mg). Thesuspension was stirred under an atmosphere of H₂ at room temperatureovernight. The Pd/C was filtered off, and washed with EtOAc. Thefiltrate was concentrated under reduced pressure and the residue waspurified by chromatography on silica gel eluting with 50% EtOAc inhexanes to give the title compound (267 mg, 97%) as a white solid. MS276 (MH⁺).

Method B:

To a solution of 3-hydroxy-2,2-dimethyl-N-propylpropanamide (20.2 g,0.127 mol) (Example 197d) in dry THF (500 mL) was carefully added NaH(60% in mineral oil, 7.64 g, 0.191 mol) in small portions at 0° C. undernitrogen. The reaction mixture was then warmed to room temperature andstirred under nitrogen for 1 hr. To this solution was slowly added atroom temperature 2-amino-6-fluorobenzonitrile (17.3 g, 0.127 mol) in THF(100 mL) and the reaction mixture refluxed overnight under nitrogen thencooled down to room temperature, quenched with brine, and extracted withEtOAc (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, evaporated and the residue was crystallized fromEtOAc/Hexane to give the compound as a white solid (16.5 g, 48%). MS 276(MH⁺).

Example 197c:3-(2-cyano-3-nitrophenoxy)-2,2-dimethyl-N-propylpropanamide

To a solution of 3-hydroxy-2,2-dimethyl-N-propylpropanamide (1.59 g,10.0 mmol) (Example 197d) in dry THF (30 mL) was carefully added NaH(60% in mineral oil, 400 mg, 10.0 mmol) in small portions at 0° C. undernitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2hrs. To this solution was added 2,6-dinitrobenzonitrile (1.93, 10.0mmol), and the reaction solution was stirred at 0° C.-RT under nitrogenovernight. The reaction mixture was quenched with brine, and extractedwith EtOAc (3×). The combined organic layers were washed with brine,dried over Na₂SO₄. After evaporation of the solvent, the residue waspurified by chromatography on silica gel eluting with 60% EtOAc inhexanes to give the title compound as a pale yellow solid (2.21 g, 72%).MS 306 (MH⁺).

Example 197d: 3-hydroxy-2,2-dimethyl-N-propylpropanamide

Method A:

A solution of methyl 3-hydroxy-2,2-dimethylpropanoate (2.64 g, 20 mmol)and n-propylamine (1.81 g, 30 mmol) was heated at 190° C. undermicrowave for 10 hrs. The excessive amine was removed under vacuum togive the title compound as colorless oil (3.18 g, 100%). MS 160 (MH⁺).

Method B:

To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (20.0 g, 0.169mol), propylamine (15.3 mL, 0.186 mol), and HOBt (25.1 g, 0.186 mol) indry dichloromethane (500 mL) was added EDCI (35.6 g, 0.186 mmol) at roomtemperature under nitrogen. The reaction mixture was then stirred atroom temperature under nitrogen overnight. The reaction quenched withbrine, and extracted EtOAc (8×). The combined organic layers were washedwith saturated NaHCO₃ solution, dilute HCl, brine, and dried overNa₂SO₄. Evaporation of the solvent under reduced pressure gave the titlecompound as colorless oil (19.2 g, 71%). MS 160 (MH⁺).

Example 198:N-(1-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2′-methylpropan-2′-yl)benzamide

Prepared as in Example 197197 fromN-(1-(3-sulfamoylamino-2-cyanophenoxy)-2-methylpropan-2-yl)benzamide(Example 198a) in 93% yield as a white solid. M.p.: 235-236° C. ¹H NMR(400 MHz, DMSO-d₆) δ 1.47 (s, 6H), 4.38 (s, 2H), 6.61 (d, J=8.4 Hz, 1H),6.77 (d, J=8.0 Hz, 1H), 7.39-7.51 (m, 4H), 7.75 (d, J=7.6 Hz, 2H), 7.90(s, 1H), 8.17 (s, 1H), 8.47 (s, 1H), 10.97 (s, 1H). MS 389 (MH⁺).

Example 198a:N-(1-(3-sulfamoylamino-2-cyanophenoxy)-2-methylpropan-2-yl)benzamide

Prepared as in Example 197a fromN-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)benzamide (Example198b) in 98% yield as a white solid. MS 389 (MH⁺).

Example 198b:N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)benzamide

Prepared as in Example 197b (Method A) fromN-(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)benzamide (Example198c) in 96% yield as a white solid. MS 310 (MH⁺).

Example 198c:N-(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)benzamide

Prepared as in Example 197c fromN-(1-hydroxy-2-methylpropan-2-yl)benzamide (Boyd, R. N.; Hansen, R. H.J. Am. Chem. Soc. 1953, 75, 5896) and 2,6-dinitrobenzonitrile in 91%yield as a pale yellow solid. MS 340 (MH⁺).

Example 199:3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-N-(2″-(benzyloxy)ethyl)-2′,2′-dimethylpropanamide

Prepared as in Example 197 from3-(3-sulfamoylamino-2-cyanophenoxy)-N-(2-(benzyloxy)ethyl)-2,2-dimethylpropanamide(Example 199a) in 92% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.22 (s, 6H), 3.26 (q, J=5.8 Hz, 2H), 3.41 (t, J=5.8 Hz, 2H), 4.07 (s,2H), 4.36 (s, 2H), 6.60 (d, J=7.6 Hz, 1H), 6.71 (d, J=7.6 Hz, 1H),7.19-7.28 (m, 4H), 7.43 (t, J=8.0 Hz, 2H), 7.91 (s, 1H), 7.97 (t, J=5.8Hz, 1H), 8.34 (s, 1H), 10.93 (s, 1H). MS 447 (MH⁺).

Example 199a:3-(3-sulfamoylamino-2-cyanophenoxy)-N-(2-(benzyloxy)ethyl)-2,2-dimethylpropanamide

Prepared as in Example 197a from3-(3-amino-2-cyanophenoxy)-N-(2-(benzyloxy)ethyl)-2,2-dimethylpropanamide(Example 199b) in 100% yield. MS 447 (MH⁺).

Example 199b:3-(3-amino-2-cyanophenoxy)-N-(2-(benzyloxy)ethyl)-2,2-dimethylpropanamide

Prepared as in Example 197b (Method B) fromN-(2-(benzyloxy)ethyl)-3-hydroxy-2,2-dimethylpropanamide (Example 199c)and 2-amino-6-fluorobenzonitrile in 82% yield. MS 368 (MH⁺).

Example 199c: N-(2-(benzyloxy)ethyl)-3-hydroxy-2,2-dimethylpropanamide

To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (2.36 g, 20 mmol),2-(benzyloxy)ethanamine (3.02 g, 20 mmol), and HOBt (2.71 g, 20 mmol) indry dichloromethane (100 mL) was added EDCI (3.82 g, 20 mmol) at roomtemperature under nitrogen. The reaction mixture was then stirred atroom temperature under nitrogen overnight. The reaction was quenchedwith brine, and extracted with EtOAc (3×). The combined organic layerswere washed with saturated NaHCO₃ solution, dilute HCl, brine, and driedover Na₂SO₄. After evaporation of the solvent, the residue was purifiedby chromatography on silica gel eluting with 40% EtOAc in hexanes togive the title compound as colorless oil (4.89 g) in 97% yield. MS 252(MH⁺).

Example 200:3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-N-(2″-hydroxyethyl)-2′,2′-dimethylpropanamide

To a solution of3-(4-amino-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2,2-dioxide-N-(2′-(benzyloxy)ethyl)-2′,2′-dimethylpropanamide(Example 199, 112 mg, 0.25 mmol) in EtOAc/EtOH/THF (1:1:1, 20.0 mL) wasadded 10% Pd/C (50 mg). And the suspension was stirred under anatmosphere of H₂ at room temperature for 2 hrs. The Pd/C was filteredoff, and washed with MeOH. The filtration was concentrated under reducedpressure, and the residue was purified by recrystallization from EtOH togive the title compound as a white solid (81 mg) in 90% yield. ¹H NMR(400 MHz, DMSO-d₆) δ 1.22 (s, 6H), 3.11 (q, J=6.0 Hz, 2H), 3.35 (q,J=6.0 Hz, 2H), 4.05 (s, 2H), 4.61 (t, J=6.0 Hz, 1H), 6.59 (d, J=8.0 Hz,1H), 6.70 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.78 (t, J=6.0 Hz,1H), 7.93 (s, 1H), 8.29 (s, 1H), 10.93 (s, 1H). MS 357 (MH⁺).

Example 201:3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-N-(4″-methoxybenzyl)-2′,2′-dimethylpropanamide

Prepared as in Example 197 from3-(3-sulfamoylamino-2-cyanophenoxy)-N-(4-methoxybenzyl)-2,2-dimethylpropanamide(Example 201a) in 92% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.25 (s, 6H), 3.66 (s, 3H), 4.12 (s, 2H), 4.21 (d, J=5.6 Hz, 2H), 6.61(d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.0 Hz, 2H), 7.06(d, J=8.0 Hz, 2H), 7.44 (t, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.31 (s, 1H),8.35 (t, J=5.6 Hz, 1H), 10.95 (s, 1H). MS 433 (MH⁺).

Example 201a:3-(3-sulfamoylamino-2-cyanophenoxy)-N-(4-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 197a from3-(3-amino-2-cyanophenoxy)-N-(4-methoxybenzyl)-2,2-dimethylpropanamide(Example 201b) in 100% yield. MS 433 (MH⁺).

Example 201b:3-(3-amino-2-cyanophenoxy)-N-(4-methoxybenzyl)-2,2-dimethylpropanamide

To a solution of3-(2-cyano-3-nitrophenoxy)-N-(4-methoxybenzyl)-2,2-dimethylpropanamide(1.15 g, 3.0 mmol) (Example 201c) in diglyme (30 mL) was added dropwisea solution of SnCl₂.2H₂O (2.03 g, 9.0 mmol) in concentrated HCl (15 mL)at 0° C. The reaction mixture was then stirred at 0° C. for another 1hr. The reaction solution was neutralized with 2 N NaOH at 0° C., andextracted with EtOAc (2×). The combined organic layers were washed withbrine, dried over Na₂SO₄. After evaporation of the solvent, the residuewas purified by chromatography on silica gel eluting with 50% EtOAc inhexanes to give the title compound as a white solid (0.91 g) in 86%yield. MS 354 (MH⁺).

Example 201c:3-(2-cyano-3-nitrophenoxy)-N-(4-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 197c from3-hydroxy-N-(4-methoxybenzyl)-2,2-dimethylpropanamide (Example 201d) and2,6-dinitrobenzonitrile in 95% yield as a pale yellow solid. MS 384(MH⁺).

Example 201d: 3-hydroxy-N-(4-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 4c from 3-hydroxy-2,2-dimethylpropanoic acid and4-methoxybenzylamine in 97% yield as a white solid. MS 238 (MH⁺).

Example 202:3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-N,2′,2′-trimethylpropanamide

Prepared as in Example 197 from3-(3-sulfamoylamino-2-cyanophenoxy)-N,2,2-trimethylpropanamide (Example202a) in 62% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.21(s, 6H), 2.58 (d, J=1.2 Hz, 3H), 4.05 (s, 2H), 6.60 (d, J=8.0 Hz, 1H),6.72 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.80 (q, J=1.2 Hz, 1H),7.96 (s, 1H), 8.33 (s, 1H), 10.93 (s, 1H). MS 327 (MH⁺).

Example 202a:3-(3-sulfamoylamino-2-cyanophenoxy)-N,2,2-trimethylpropanamide

Prepared as in Example 197a from3-(3-amino-2-cyanophenoxy)-N,2,2-trimethylpropanamide (Example 202b) in69% yield. MS 327 (MH⁺).

Example 202b: 3-(3-amino-2-cyanophenoxy)-N,2,2-trimethylpropanamide

Prepared as in Example 197b (Method A) from3-(2-cyano-3-nitrophenoxy)-N,2,2-trimethylpropanamide (Example 202c) in95% yield as a white solid. MS 248 (MH⁺).

Example 202c: 3-(2-cyano-3-nitrophenoxy)-N,2,2-trimethylpropanamide

Prepared as in Example 197c from 3-hydroxy-N,2,2-trimethylpropanamide(Example 202d) and 2,6-dinitrobenzonitrile in 77% yield as a pale yellowsolid. MS 378 (MH⁺).

Example 202d: 3-hydroxy-N,2,2-trimethylpropanamide

Prepared as in Example 197d from methyl 3-hydroxy-2,2-dimethylpropanoateand methylamine in 51% yield. MS 132 (MH⁺).

Example 203:3-(4-amino-2-oxo-1,2-dihydroquinazolin-5-yloxy)-2,2-dimethyl-N-propylpropanamide

A solution ofN-(2-cyano-3-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-phenylcarbamoyl)benzamide(example 203a) (141 mg, 0.3 mmol) and NaOH (2 N, 0.3 mL) in EtOH (5 mL)was stirred at 100° C. under nitrogen for 2 hrs. After cooling to roomtemperature, the clear reaction solution was filtered, and the filtratewas carefully neutralized with 10% AcOH with vigorous stirring at 0° C.The resultant precipitate was collected by filtration, washed with waterand then 20% EtOH in water to give the final product (81 mg) in 76%yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.73 (t, J=7.4Hz, 3H), 1.21 (s, 6H), 1.33-1.41 (m, 2H), 3.01 (q, J=7.4 Hz, 2H), 4.08(s, 2H), 6.64 (d, J=8.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0Hz, 1H), 7.47 (s, 1H), 7.79 (t, J=7.4 Hz, 1H), 7.84 (s, 1H), 10.60 (s,1H). MS 319 (MH⁺).

Example 203a:N-(2-cyano-3-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)phenyl-carbamoyl)benzamide

Prepared as in Example 24a from3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide (Example197b, Method A) and benzoyl isocyanate in 85% yield as a white solid. MS423 (MH⁺).

Example 204:3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-N-(2″-methoxyethyl)-2′,2′-dimethylpropanamide

Prepared as in Example 197 from3-(3-sulfamoylamino-2-cyanophenoxy)-N-(2-methoxyethyl)-2,2-dimethylpropanamide(Example 204a) in 12% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.21 (s, 6H), 3.13 (s, 3H), 3.17-3.22 (m, 2H), 3.28 (t, J=6.0 Hz, 2H),4.07 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.43 (t,J=8.0 Hz, 1H), 7.87 (s, 1H), 7.91 (t, J=5.6 Hz, 1H), 8.33 (s, 1H), 10.92(s, 1H). MS 371 (MH⁺).

Example 204a:3-(3-sulfamoylamino-2-cyanophenoxy)-N-(2-methoxyethyl)-2,2-dimethylpropanamide

Prepared as in Example 197a from3-(3-amino-2-cyanophenoxy)-N-(2-methoxyethyl)-2,2-dimethylpropanamide(Example 204b) in 41% yield. MS 371 (MH⁺).

Example 204b:3-(3-amino-2-cyanophenoxy)-N-(2-methoxyethyl)-2,2-dimethylpropanamide

Prepared as in Example 197b (Method A) from3-(2-cyano-3-nitrophenoxy)-N-(2-methoxyethyl)-2,2-dimethylpropanamide(Example 204c) in 91% yield. MS 292 (MH⁺).

Example 204c:3-(2-cyano-3-nitrophenoxy)-N-(2-methoxyethyl)-2,2-dimethylpropanamide

Prepared as in Example 197c from3-hydroxy-N-(2-methoxyethyl)-2,2-dimethylpropanamide (Example 204d) and2,6-dinitrobenzonitrile in 55% yield. MS 322 (MH⁺).

Example 204d: 3-hydroxy-N-(2-methoxyethyl)-2,2-dimethylpropanamide

Prepared as in Example 197d (Method A) from methyl3-hydroxy-2,2-dimethylpropanoate and 2-methoxyethanamine in 100% yield.MS 30 (MH⁺).

Example 205:N-(3-(4-amino-)-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy-2′,2′-dimethylpropyl)propionamide

Prepared as in Example 197a fromN-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)propionamide (Example205a) and sulfamoyl chloride in 17% yield as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 0.93-0.96 (m, 9H), 2.06-2.11 (m, 2H), 3.07 (d, J=6.0 Hz,2H), 3.74 (s, 2H), 6.58 (t, J=8.4 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.41(t, J=8.4 Hz, 1H), 7.93-7.98 (m, 2H), 8.35 (brs, 1H), 10.91 (brs, 1H).MS 355 (MH⁺).

Example 205a:N-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)propionamide

Prepared as in Example 197b (Method A) fromN-(3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropyl)propionamide (Example205b) in 100% yield. MS 276 (MH⁺).

Example 205b:N-(3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropyl)propionamide

Prepared as in Example 197c fromN-(3-hydroxy-2,2-dimethylpropyl)propionamide (Example 205c) and2,6-dinitrobenzonitrile in 68% yield. MS 306 (MH⁺).

Example 205c: N-(3-hydroxy-2,2-dimethylpropyl)propionamide

Prepared according to the literature (Boyd, R. N.; Hansen, R. H. J. Am.Chem. Soc. 1953, 75, 5896) from 2-amino-2-methylpropan-1-ol and benzoylchloride in 84% yield as a white solid. MS 160 (MH⁺).

Example 206:1-(3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2′,2′-dimethylpropyl)-3′-ethylurea

Prepared as in Example 197 from1-(3-(3-sulfamoylamino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-ethylurea(Example 206a) in 55% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 0.88-0.96 (m, 9H), 2.90-2.97 (m, 2H), 3.01 (d, J=6.4 Hz, 2H), 3.72 (s,2H), 5.75 (t, J=5.6 Hz, 1H), 6.07 (t, J=6.4 Hz, 1H), 6.56 (d, J=8.4 Hz,1H), 6.67 (d, J=8.8 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 8.05 (brs, 1H),8.25 (brs, 1H), 10.89 (s, 1H). MS 370 (MH⁺).

Example 206a:1-(3-(3-sulfamoylamino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-ethylurea

Prepared as in Example 197a from1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-ethylurea (Example206b) in 100% yield. MS 370 (MH⁺).

Example 206b:1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-ethylurea

Prepared as in Example 197b (Method A) from1-(3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropyl)-3-ethylurea (Example206c) in 90% yield. MS 291 (MH⁺).

Example 206c:1-(3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropyl)-3-ethylurea

Prepared as in Example 197c from1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)urea (Example 206d) and2,6-dinitrobenzonitrile in 47% yield. MS 321 (MH⁺).

Example 206d: 1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)urea

To a solution of 3-amino-2,2-dimethylpropan-1-ol (1.03 g, 10 mmol) indry 1,4-dioxane (20 mL) was added dropwise ethyl isocyanate (0.71 g, 10mmol) at room temperature under nitrogen. The reaction mixture was thenstirred at room temperature under nitrogen overnight.

The solvent was removed under reduced pressure to give the titlecompound as colorless oil (1.74 g, 100%). MS 175 (MH⁺).

Example 207:3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-N-butyl-2′,2′-dimethylpropanamide

Prepared as in Example 197 and 1a from3-(3-amino-2-cyanophenoxy)-N-butyl-2,2-dimethylpropanamide (Example207a) and sulfamoyl chloride in 14% yield as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 0.78 (t, J=7.2 Hz, 3H), 1.14-1.22 (m, 8H), 1.33-1.37 (m,2H), 3.02-3.07 (m, 2H), 4.07 (s, 2H), 6.60 (d, J=8.0 Hz, 1H), 6.71 (d,J=8.8 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 7.91 (s,1H), 8.33 (s, 1H), 10.92 (s, 1H). MS 369 (MH⁺).

Example 207a: 3-(3-amino-2-cyanophenoxy)-N-butyl-2,2-dimethylpropanamide

Prepared as in Example 197b (Method A) fromN-butyl-3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropanamide (Example207b) in 89% yield. MS 290 (MH⁺).

Example 207b: N-butyl-3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropanamide

Prepared as in Example 197c fromN-butyl-3-hydroxy-2,2-dimethylpropanamide (Example 207c) and2,6-dinitrobenzonitrile in 66% yield. MS 320 (MH⁺).

Example 207c: N-butyl-3-hydroxy-2,2-dimethylpropanamide

Prepared as in Example 197d (Method A) from methyl3-hydroxy-2,2-dimethylpropanoate and n-butyl amine in 100% yield. MS 174(MH⁺).

Example 208:N-(1-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2′-methylpropan-2′-yl)butyramide

Prepared as in Example 197 fromN-(1-(3-sulfamoylamino-2-cyanophenoxy)-2-methylpropan-2-yl)butyramide(Example 208a) and sodium hydroxide in 54% yield as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 0.78 (t, J=7.2 Hz, 3H), 1.32 (s, 6H), 1.43-1.44(m, 2H), 2.00 (t, J=7.2 Hz, 2H), 4.24 (s, 2H), 6.60 (d, J=8.0 Hz, 1H),6.73 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.82 (s,1H), 8.42 (s, 1H), 10.97 (s, 1H). MS 355 (MH⁺).

Example 208a:N-(1-(3-sulfamoylamino-2-cyanophenoxy)-2-methylpropan-2-yl)-butyramide

Prepared as in Example 197a fromN-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)butyramide (Example208b) and sulfamoyl chloride in 100% yield. MS 355 (MH⁺).

Example 208b:N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)butyramide

Prepared as in Example 197b (Method A) fromN-(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)butyramide (Example208c) in 100% yield. MS 276 (MH⁺).

Example 208c:N-(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)butyramide

Prepared as in Example 197c fromN-(1-hydroxy-2-methylpropan-2-yl)butyramide (Example 208d) and2,6-dinitrobenzonitrile in 72% yield. MS 306 (MH⁺).

Example 208d: N-(1-hydroxy-2-methylpropan-2-yl)butyramide

Prepared according to the literature (Boyd, R. N.; Hansen, R. H. J. Am.Chem. Soc. 1953, 75, 5896) from 2-amino-2-methylpropan-1-ol and butyrylchloride in 32% yield. MS 160 (MH⁺).

Example 209:1-(1-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2′-methylpropan-2′-yl)-3′-ethylurea

Prepared as in Example 197 from1-(1-(3-sulfamoylamino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea(Example 209a) in 37% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 0.92 (t, J=7.2 Hz, 3H), 1.27 (s, 6H), 2.90-2.93 (m, 2H), 4.21 (s, 2H),5.63 (t, J=5.2 Hz, 1H), 5.95 (s, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.72 (d,J=8.4 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.94 (s, 1H), 8.34 (s, 1H), 10.94(s, 1H). MS 356 (MH⁺).

Example 209a:1-(1-(3-sulfamoylamino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea

Prepared as in Example 197a from1-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea (Example209b) and sulfamoyl chloride in 100% yield. MS 356 (MH⁺).

Example 209b:1-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea

Prepared as in Example 197b (Method A) from1-(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)-3-ethylurea (Example209c) in 86% yield. MS 277 (MH⁺).

Example 209c:1-(1-(2-cyano-3-nitrophenoxy)-2-methylpropan-2-yl)-3-ethylurea

Prepared as in Example 197c from1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)urea (Example 209d) and2,6-dinitrobenzonitrile in 65% yield. MS 307 (MH⁺).

Example 209d: 1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)urea

Prepared as in Example 206d from 2-amino-2-methylpropan-1-ol and ethylisocyanate in 94% yield. MS 161 (MH⁺).

Example 210:N-(4-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)butyl)-acetamide

Prepared as in Example 197 fromN-(4-(2-cyano-3-(sulfamoylamino)phenoxy)butyl)acetamide (Example 210a)in 30% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.48-1.51 (m, 2H), 1.77-1.81(m, 5H), 3.03-3.08 (m, 2H), 4.14 (t, J=6.0 Hz, 2H), 6.59 (d, J=8.0 Hz,1H), 6.73 (d, J=8.4 Hz, 1H), 7.43 (t, J=8.4 Hz, 1H), 7.78 (s, 1H). 7.84(brs, 1H), 8.32 (s, 1H), 10.93 (s, 1H). MS 327 (MH⁺).

Example 210a: N-(4-(2-cyano-3-(sulfamoylamino)phenoxy)butyl)acetamide

Prepared as in Example 197a fromN-(4-(3-amino-2-cyanophenoxy)butyl)acetamide (Example 210b) andsulfamoyl chloride in 100% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.51-1.54(m, 2H), 1.70-1.73 (m, 2H), 1.77 (s, 3H), 3.04-3.09 (m, 2H), 4.09 (t,J=6.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (s,2H), 7.54 (t, J=8.0 Hz, 1H), 7.85 (brs, 1H), 9.42 (s, 1H).

Example 210b: N-(4-(3-amino-2-cyanophenoxy)butyl)acetamide

Prepared as in Example 197b (Method A) fromN-(4-(2-cyano-3-nitrophenoxy)butyl)acetamide (Example 210c) in 85%yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.54 (m, 2H), 1.66-1.70 (m, 2H),1.77 (s, 3H), 3.03-3.08 (m, 2H), 3.97 (t, J=6.8 Hz, 2H), 5.95 (s, 2H),6.18 (d, J=8.0 Hz, 1H), 6.31 (d, J=7.6 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H),7.83 (brs, 1H).

Example 210c: N-(4-(2-cyano-3-nitrophenoxy)butyl)acetamide

To a solution of 2-(4-aminobutoxy)-6-nitrobenzonitrile (Example 210d)(235 mg, 1.0 mmol), triethylamine (3 equiv.), and DMAP (0.1 equiv.) indry dichloromethane (20 mL) was added dropwise acetyl chloride (1.5equiv.) at 0° C. under nitrogen. The reaction mixture was then stirredat 0° C.-RT overnight. The reaction was diluted with EtOAc, washed withbrine, and dried over Na₂SO₄. After evaporation of the solvent, theresidue was purified by chromatography on silica gel eluting with 50%EtOAc in hexanes to give the title compound (158 mg, 57%). MS 278 (MH⁺).

Example 210d: 2-(4-aminobutoxy)-6-nitrobenzonitrile

A solution of tert-butyl 4-(2-cyano-3-nitrophenoxy)butylcarbamate(Example 210e) (671 mg, 2 mmol) in DCM/TFA (1:1, 20 mL) was stirred atroom temperature for 2 hrs. The solvent was removed under vacuum to givethe title compound (698 mg, 100%). MS 236 (MH⁺).

Example 210e: tert-butyl 4-(2-cyano-3-nitrophenoxy)butylcarbamate

Prepared as in Example 197c from tert-butyl 4-hydroxybutylcarbamate and2,6-dinitrobenzonitrile in 7% yield as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 1.35 (s, 9H), 1.52-1.55 (m, 2H), 1.72-1.76 (m, 2H),2.94-2.99 (m, 2H), 4.24 (t, J=6.8 Hz, 2H), 6.86 (brs, 1H), 7.69-7.72 (m,1H), 7.85-7.90 (m, 2H).

Example 211:4-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)butylSulfamate

Prepared as in Example 197 from4-(2-cyano-3-(sulfamoylamino)phenoxy)butyl sulfamate (Example 211a) in31% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.74-1.79 (m, 2H), 1.85-1.91 (m,2H), 4.07 (t, J=6.4 Hz, 2H), 4.18 (t, J=6.8 Hz, 2H), 6.58-6.60 (m, 1H),6.74 (d, J=8.4 Hz, 1H), 7.42-7.46 (m, 3H), 7.79 (s, 1H), 8.32 (s, 1H),10.93 (s, 1H). MS 365 (MH⁺).

Example 211a: 4-(2-cyano-3-(sulfamoylamino)phenoxy)butyl sulfamate

Prepared as in Example 197a from2-amino-6-(4-(tert-butyldimethylsilyloxy)butoxy)benzonitrile (Example211b) and sulfamoyl chloride in 63% yield. MS 382 (M++H₂O).

Example 211b:2-amino-6-(4-(tert-butyldimethylsilyloxy)butoxy)benzonitrile

Prepared as in Example 197b (Method A) from2-(4-(tert-butyldimethylsilyloxy)butoxy)-6-nitrobenzonitrile (Example211c) in 76% yield. MS 321 (MH⁺).

Example 211c:2-(4-(tert-butyldimethylsilyloxy)butoxy)-6-nitrobenzonitrile

Prepared as in Example 197c from4-(tert-butyldimethyl-silyloxy)butan-1-ol and 2,6-dinitrobenzonitrile in25% yield as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.01 (s,6H), 0.81-0.83 (m, 9H), 1.61-1.66 (m, 2H), 1.76-1.81 (m, 2H), 3.63 (t,J=6.8 Hz, 2H), 4.26 (t, J=6.4 Hz, 2H), 7.68-7.70 (m, 1H), 7.84-7.89 (m,2H).

Example 212:6-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexylSulfamate

Prepared as in Example 197 from6-(2-cyano-3-(sulfamoylamino)phenoxy)hexyl sulfamate (Example 212a) in46% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.03-1.05 (m, 4H), 1.28 (m, 2H),1.45 (m, 2H), 3.64 (t, J=6.4 Hz, 2H), 3.78 (t, J=6.4 Hz, 2H), 6.22 (d,J=7.6 Hz, 1H), 6.37 (d, J=7.6 Hz, 1H), 7.02 (s, 2H), 7.07 (t, J=7.6 Hz,1H), 7.44 (s, 1H), 7.96 (s, 1H), 10.56 (s, 1H). MS 393 (MH⁺).

Example 212a: 6-(2-cyano-3-(sulfamoylamino)phenoxy)hexyl sulfamate

Prepared as in Example 197a from2-amino-6-(6-hydroxy-hexyloxy)benzonitrile (Example 212b) and sulfamoylchloride in 20% yield. MS 393 (MH⁺).

Example 212b: 2-amino-6-(6-hydroxyhexyloxy)benzonitrile

Prepared as in Example 197b (Method A) from2-(6-hydroxyhexyloxy)-6-nitrobenzonitrile (Example 212c) in 99% yield.MS 235 (MH⁺).

Example 212c: 2-(6-hydroxyhexyloxy)-6-nitrobenzonitrile

Prepared as in Example 197c from hexane-1,6-diol and2,6-dinitrobenzonitrile in 88% yield as a pale yellow solid. MS 265(MH⁺).

Example 213:5-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)pentylsulfamate

Prepared as in Example 197 from5-(2-cyano-3-(sulfamoylamino)-phenoxy)pentyl sulfamate (Example 213a) in44% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.09 (m, 2H), 1.33 (m, 2H), 1.47(m, 2H), 3.66 (t, J=6.6 Hz, 2H), 3.79 (t, J=6.6 Hz, 2H), 6.22 (d, J=8.0Hz, 1H), 6.37 (d, J=8.0 Hz, 1H), 7.03 (s, 2H), 7.07 (t, J=8.0 Hz, 1H),7.43 (s, 1H), 7.95 (s, 1H), 10.57 (s, 1H). MS 379 (MH⁺).

Example 213a: 5-(2-cyano-3-(sulfamoylamino)phenoxy)pentyl Sulfamate

Prepared as in Example 197a from2-amino-6-(5-(tert-butyldimethylsilyloxy)pentyloxy)benzonitrile (Example213b) and sulfamoyl chloride in 26% yield. MS 379 (MH⁺).

Example 213b:2-amino-6-(5-(tert-butyldimethylsilyloxy)pentyloxy)benzonitrile

Prepared as in Example 197b (Method A) from2-(5-(tert-butyldimethyl-silyloxy)pentyloxy)-6-nitrobenzonitrile(Example 213c) in 93% yield. MS 335 (MH⁺).

Example 213c:2-(5-(tert-butyldimethylsilyloxy)pentyloxy)-6-nitrobenzonitrile

Prepared as in Example 197c from5-(tert-butyldimethyl-silyloxy)pentan-1-ol and 2,6-dinitrobenzonitrileas a pale yellow solid in 46% yield. MS 365 (MH⁺).

Example 214:5-(4-(methylsulfinyl)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

To a solution of5-(4-(methylthio)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide(Example 233) (79 mg, 0.25 mmol) in DCM/CH₃CO₂H (20:1, 20 mL) was addedMCPBA (1.0 equiv.) at room temperature. The reaction mixture was thenstirred at room temperature overnight. The solvent was evaporated underreduced pressure, and the residue was purified by chromatography onsilica gel eluting with 15% MeOH in dichloromethane to give the titlecompound (74 mg, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.74-1.77 (m, 2H), 1.88-1.95 (m, 2H), 2.50 (s, 3H), 2.68-2.73 (m, 1H),2.77-2.83 (m, 1H), 4.19 (t, 2H), 6.58-6.60 (d, J=8.4 Hz, 1H), 6.73-6.75(d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 8.33 (s, 1H),10.92 (s, 1H). MS 332 (MH⁺).

Example 215:5-(4-(methylsulfonyl)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 214 from5-(4-(methylthio)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide(Example 98) by the reaction with 3 equivalent of MCPBA as a white solidin 88% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.80-1.82 (m, 2H), 1.91-1.95(m, 2H), 2.93 (s, 3H), 3.18 (t, 2H), 4.18 (t, 2H), 6.58-6.60 (d, J=8.4Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.79 (s,1H), 8.34 (s, 1H), 10.92 (s, 1H). MS 348 (MH⁺).

Example 216:5-(3-(methylsulfinyl)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 214 from5-(3-(methylthio)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide(Example 99) by the reaction with 1.0 equivalent of MCPBA as a whitesolid in 90% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 2.18-2.22 (m, 2H), 2.54(s, 3H), 2.75-2.78 (m, 1H), 2.89-2.93 (m, 1H), 4.26 (t, J=6.4 Hz, 2H),6.60-6.61 (d, J=8.4 Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0Hz, 1H), 7.83 (s, 1H), 8.30 (s, 1H), 10.92 (s, 1H). MS 318 (MH⁺).

Example 217:5-(3-(methylsulfonyl)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 214 from5-(3-(methylthio)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide(Example 99) by the reaction with 3.0 equivalent of MCPBA in 87% yieldas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.24-2.27 (m, 2H), 3.00(s, 3H), 3.26 (t, J=7.6 Hz, 2H), 4.24 (t, J=6.4 Hz, 2H), 6.60-6.62 (d,J=8.0 Hz, 1H), 6.72-6.74 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.79(s, 1H), 8.31 (s, 1H), 10.93 (s, 1H). MS 334 (MH⁺).

Example 218:1-(3-(4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)-2′,2′-dimethylpropyl)-3′-(4″-methoxybenzyl)urea

Prepared as in Example 197 from1-(3-(3-sulfamoylamino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea(Example 218a) in 77% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 0.92 (s, 6H), 3.06 (d, J=6.4 Hz, 2H), 3.32 (s, 2H), 3.67 (s, 3H), 4.06(d, J=6.0 Hz, 2H), 6.29 (t, J=6.0 Hz, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.71(d, J=8.0 Hz, 1H), 6.74 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 7.44(t, J=8.0 Hz, 1H), 8.12 (s, 1H), 8.34 (s, 1H), 10.90 (s, 1H). MS 462(MH⁺).

Example 218a:1-(3-(3-sulfamoylamino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea

Prepared as in Example 197a from1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea(Example 218b) and sulfamoyl chloride in 100% yield. MS 462 (MH⁺).

Example 218b:1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea

Prepared as in Example 197b (Method B) from1-(3-hydroxy-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 218c)and 2-amino-6-fluorobenzonitrile in 60% yield. MS 383 (MH⁺).

Example 218c: 1-(3-hydroxy-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea

Prepared as in Example 206d from 3-amino-2,2-dimethylpropan-1-ol and4-methoxybenzyl isocyanate in 100% yield. MS 267 (MH⁺).

Example 219:1-(2-(4-amino-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)ethyl)pyrrolidin-2-one-2,2-dioxide

Prepared as in Example 158 from2-amino-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile sulfamide(Example 219a) in 45% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.94 (q, J=7.2Hz, 2H), 2.26 (t, J=7.6 Hz, 2H), 3.43 (t, J=7.2 Hz, 2H), 3.68 (t, J=4.4Hz, 2H), 4.23 (t, J=4.4 Hz, 2H), 6.59 (d, J=7.6 Hz, 1H), 6.70 (d, J=8.8Hz, 1H), 7.43 (t, J=8.4 Hz, 1H), 7.82 (bs, NH), 8.21 (bs, NH), 10.98(bs, NH). MS 325 (MH⁺).

Example 219a: 2-amino-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrilesulfamide

Prepared as in Example 157a from2-amino-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile (Example 219b) in100% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.94 (q, J=8.4 Hz, 2H), 2.22 (t,J=8.4 Hz, 2H), 3.50-3.58 (m, 4H), 4.21 (t, J=4.8 Hz, 2H), 6.94 (bs, 1H),7.17 (d, J=7.6 Hz, 1H), 7.24 (bs, NH₂), 7.54 (t, J=7.2 Hz, 1H), 9.49(bs, NH). MS 325 (MH⁺).

Example 219b: 2-amino-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile

Prepared as in example 235b from2-nitro-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile (Example 219c)using trifluoroethanol/hexafluoroisopropanol (1:1) as solvent in 100%yield MS 246 (MH⁺).

Example 219c: 2-nitro-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzonitrile

Prepared as in Example 160d from 1-(2-hydroxyethyl)pyrrolidin-2-one and2,6-dinitrobenzonitrile in 74% yield. MS 276 (MH⁺).

Example 220:3-((4-Amino-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)methyl)-N-propylpiperidine-1-carboxamide-2,2-dioxide

Prepared as in Example 158 from3-((3-amino-2-cyanophenoxy)methyl)-N-propylpiperidine-1-carboxamidesulfamide (Example 220a) in 88% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81(t, J=6.8 Hz, 3H), 1.23-1.43 (m, 4H), 1.60-1.63 (bm, 1H), 1.81-1.84 (bm,1H), 1.99-2.05 (bm, 1H), 2.67-2.75 (m, 1H), 2.80-2.85 (m, 1H), 2.93-2.98(m, 2H), 3.71 (bd, J=12.8, 1H), 3.90 (bd, J=10.8, 1H), 3.98-4.08 (m,2H), 6.44 (d, J=6.0 Hz, NH), 6.62 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.4 Hz,1H), 7.46 (t, J=8.4 Hz, 1H), 7.80 (s, NH), 8.37 (s, NH), 10.95 (s, NH).MS 396 (MH⁺).

Example 220a: 3-((3-amino-2-cyanophenoxy)methyl)-N-propylpiperidine-1carboxamide sulfamide

Prepared as in Example 157a from3-((3-amino-2-cyanophenoxy)methyl)-N-propylpiperidine-1-carboxamide(Example 220b) in 100% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=7.2Hz, 3H), 1.31-1.44 (m, 4H), 1.61-1.64 (bm, 1H), 1.85-1.87 (bm, 2H),2.60-2.75 (m, 2H), 2.94-2.98 (m, 2H), 3.78 (bd, J=12.8 Hz, 1H),3.93-3.97 (m, 1H), 4.01-4.10 (m, 2H), 6.38 (d, J=6.0 Hz, NH), 6.96 (d,J=8.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.27 (s, NH), 7.41 (s, NH), 7.57(t, J=8.4 Hz, 1H), 9.48 (s, NH). MS 396 (MH⁺).

Example 220b:3-((3-amino-2-cyanophenoxy)methyl)-N-propylpiperidine-1-carboxamide

Prepared as in Example 235b from3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide(Example 220c) in 94% yield. MS 317 (MH⁺).

Example 220c:3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide

To a solution of 2-nitro-6-(piperidin-3-ylmethoxy)benzonitrilehydrochloride (Example 220d) (0.10 g, 0.34 mmol) in THF (6 mL) wereadded triethylamine (0.10 mL, 0.76 mmol) and propylisocyanate (0.05 mL,0.52 mmol) and the reaction mixture was stirred at r.t. under nitrogenfor 3 hour then filtered and evaporated, to give3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide(0.13 g, 100%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=7.2 Hz, 3H),1.34-1.41 (m, 4H), 1.62-1.64 (bm, 1H), 1.87-1.95 (bm, 2H), 2.64-2.77 (m,2H), 2.93-2.98 (m, 2H), 3.77 (bd, J=12.8 Hz, 1H), 3.98 (bd, J=12.8 Hz,1H), 4.09-4.13 (m, 1H), 4.17-4.20 (m, 1H), 6.38 (d, J=5.6 Hz, NH), 7.74(bdd, J=1.6 Hz, J=8.0 Hz, 1H), 7.88-7.94 (m, 2H). MS 347 (MH⁺).

Example 220d: 2-nitro-6-(piperidin-3-ylmethoxy)benzonitrileHydrochloride

Prepared as in Example 160 from tert-butyl3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example220e) in 98% yield. MS 262 (MH⁺).

Example 220e: tert-butyl3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 197c from tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate and 2,6-dinitrobenzonitrile in58% yield. MS 263 [M+H-Boc]⁺.

Example 221: Tert-butyl3-((4-amino-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)methyl)piperidine-1-carboxylate-2,2-dioxide

Prepared as in Example 158 from tert-butyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate sulfamide(Example 221a), keeping the pH above 3 upon acidification, to givetert-butyl3-((4-amino-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)methyl)piperidine-1-carboxylate-2,2-dioxide(33 mg, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27-1.40 (bs, 11H), 1.62-1.66(bm, 1H), 1.78-1.83 (bm, 1H), 2.05-2.12 (bm, 1H), 2.87-2.94 (m, 2H),3.64-3.71 (bm, 1H), 3.83-3.86 (bm, 1H), 4.04 (bd, J=7.2 Hz, 2H), 6.62(d, J=8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.76(bs, NH), 8.37 (bs, NH), 10.95 (s, NH). MS 311 [M+H-Boc]⁺.

Example 221a: tert-butyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate Sulfamide

Prepared as in Example 157a from tert-butyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example221b). Upon extraction, NaOH 1M (1.56 mL, 1.56 mmol) was added to theice-cooled reaction medium triggering formation of a sticky orangymaterial. Water was poured away and the residue diluted in EtOAc, andextracted, to give tert-butyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate sulfamide(0.15 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.35-1.40 (bs, 11H),1.63-1.66 (bm, 1H), 1.79-1.83 (bm, 1H), 1.88-1.93 (bm, 1H), 2.78-2.85(m, 2H), 3.74-3.78 (bm, 1H), 3.92-4.04 (m, 3H), 6.96 (d, J=8.4 Hz, 1H),7.15 (d, J=8.4 Hz, 1H), 7.27 (s, NH₂), 7.56 (t, J=8.8 Hz, 1H), 9.47 (s,NH). MS 311 [M+H-Boc]⁺.

Example 221b: tert-butyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in example 100b from tert-butyl3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example220e) in 100% yield as an oil. MS 232 [M+H-Boc]⁺.

Example 222:4-Amino-5-(((2R,3S,4R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

To a solution of4-Amino-5-(((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide(Example 212a) (7 mg, 0.020 mmol) in dry methanol (1 mL) was addedtrifluoroacetic acid 0.2 mL) and the mixture was refluxed overnight. Theresulting solution was evaporated to dryness to provide the titlecompound as a white powder (7.28 mg, 100%, mixture of diastereomers˜4/1). ¹H NMR (400 MHz, DMSO-d₆): δ [3.17 (s, H)], 3.22 (s, 3H), 3.81(d, J=4.0 Hz, 1H), [3.93 (m, ½H)], 4.12 (m, 3H), 4.39 (m, 1H), 4.71 (s,1H), [4.85 (d, J=4.0 Hz, H)], 5.44 (br s, 2H), 6.65 (d, J=8.0 Hz, 1H),6.81 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.95 (s, 1H), 8.41 (s,1H), 11.00 (s, 1H), [11.01 (s, 4H)].

Example 222a:4-Amino-5-(((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

To a suspension of4-Amino-5-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide(Example 212b) (15 mg, 0.038 mmol) in water (1 mL) was addedtrifluoroacetic acid (0.2 mL) and the mixture was heated overnight at80° C. The reaction mixture was evaporated to dryness to furnish thetitle compound as a white solid in quantitative yield (mixture ofdiastereomers ˜10/1). ¹H NMR (400 MHz, DMSO-d₆): δ 3.71 (m, 4H), 4.12(m, 3H), 4.35 (m, 1H), 5.02 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.79 (d,J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 8.03 (br s, 1H), 8.31 (br s, 1H),10.96 (br s, 1H), [11.00 (br s, 0.1H)].

Example 222b:4-Amino-5-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 158 from2-sulfamoylamino-6-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)benzonitrile(Example 212c) in 78% yield as a beige solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.28 (s, 3H), 1.41 (s, 3H), 3.18 (s, 3H), 4.00 (t, J=9.2 Hz, 1H), 4.32(dd, J=5.2, 10.0 Hz, 1H), 4.59 (dd, J=5.2, 8.8 Hz, 1H), 4.63 (d, J=6.0Hz, 1H), 4.82 (d, J=6.0 Hz, 1H), 5.02 (s, 1H), 6.64 (d, J=8.4 Hz, 1H),6.70 (d, J=8.4 Hz, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.98 (br s, 1H), 8.43(br s, 1H), 11.02 (br s, 1H).

Example 222c:2-Sulfamoylamino-6-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)benzonitrile

Prepared as in Example 158a from2-amino-6-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)benzonitrile(Example 212d) in 77% yield as a white solid. ¹H NMR (400 MHz, CDCl₃) δ1.34 (s, 3H), 1.50 (s, 3H), 3.33 (s, 3H), 4.08 (m, 2H), 4.51 (dd, J=6.4,7.6 Hz, 1H), 4.65 (d, J=6.0 Hz, 1H), 4.79 (d, J=6.0 Hz, 1H), 5.01 (s,1H), 5.25 (br s, 2H), 6.70 (d, J=8.4 Hz, 1H), 7.28 (br s, 1H), 7.30 (d,J=8.0 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H).

Example 222d:2-Amino-6-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-(((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-6-nitrobenzonitrile(Example 212e) in 40% yield as colorless sticky material. ¹H NMR (400MHz, CDCl₃) δ 1.33 (s, 3H), 1.49 (s, 3H), 3.33 (s, 3H), 4.05 (m, 2H),4.45 (br s, 2H), 4.56 (dd, J=6.0, 8.0 Hz, 1H), 4.65 (d, J=6.0 Hz, 1H),4.82 (br d, J=6.0 Hz, 1H), 5.00 (s, 1H), 6.21 (dd, J=0.8, 8.4 Hz, 1H),6.33 (dd, J=0.8, 8.4 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H).

Example 222e:2-(((3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-6-nitrobenzonitrile

Prepared as in Example 158c from 2,6 dinitrobenzonitrile and((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanolin 70% yield as white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.33 (s, 3H),1.49 (s, 3H), 3.32 (s, 3H), 4.23 (d, J=2.0 Hz, 1H), 4.24 (s, 1H), 4.60(br t, J=6.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 1H), 4.86 (br d, J=6.0 Hz, 1H),5.01 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.72 (t, J=8.4 Hz, 1H), 7.87 (dd,J=0.8, 8.4 Hz, 1H).

Example 223:4-Amino-5-(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

Prepared as in Example 236 from2-amino-6-(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy)benzonitrile(Example 213a) in 72% yield as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (s, 3H), 1.43 (s, 3H), 4.07 (m, 2H),4.19 (br d, J=8.4 Hz, 1H), 4.36 (dd, J=1.2, 8.0 Hz, 1H), 4.41 (dd,J=2.4, 5.2 Hz, 1H), 4.44 (dd, J=2.4, 10.0 Hz, 1H), 4.67 (dd, J=2.4, 8.0Hz, 1H), 5.51 (d, J=4.8 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 7.86 (br s, 1H), 8.41 (br s, 1H), 10.98(br s, 1H). MS 456 (MH⁺).

Example 223a:2-Amino-6-(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy)benzonitrile

Prepared as in Example 158b from2-nitro-6-(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy)benzonitrile(Example 213b) in quantitative yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.28(s, 3H), 1.31 (s, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 4.05 (m, 2H), 4.16(dd, J=4.0, 8.8 Hz, 1H), 4.37 (m, 2H), 4.67 (dd, J=2.4, 8.0 Hz, 1H),5.47 (d, J=4.8 Hz, 1H), 6.01 (br s, 2H), 6.23 (d, J=8.0 Hz, 1H), 6.35(d, J=8.4 Hz, 1H), 7.17 (t, J=8.4 Hz, 1H).

Example 223b:2-Nitro-6-(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methoxy)benzonitrile

Prepared as in Example 158c from 2,6 dinitrobenzonitrile and((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl)methanolin 59% yield as white sticky material. MS 408 (MH⁺), 424 (MH₂O⁺).

Example 224:8-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)octan-1-ol

To a solution of 8-(3-amino-2-cyanophenoxy)octyl acetate (746 mol, 227mg) in DMA (3 mL) was added sulfamoyl chloride (1.492 mmol, 172 mg) andpyridine (4.476 mmol, 362 μL). The reaction mixture was stirred at roomtemperature until completion, then quenched with sat. NaHCO₃ (15 mL) andsolid NaCl added. The precipitate was collected and washed with water.The wet precipitate was suspended in EtOH (15 mL) and treated with NaOH(8.952 mmol, 1N, 8.95 mL). The reaction mixture was refluxed untilcompletion then cooled to room temperature. Most of the EtOH and waterwere removed in vacuo, then the reaction mixture was dissolved in water(15 mL), extracted with ether (3×5 mL), filtered through a 0.45 m PTFEfrit, then acidified with 10% citric acid/water solution to pH 4-5. Theprecipitate was filtered off, washed with water and dried to give thedesired product 146 mg (57.3%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ1.265 (m, 6H), 1.380 (m, 4H), 1.785 (pentet, J=7 Hz, 2H),3.348 (q, J=6 Hz, 2H), 4.303 (t, J=5 Hz, 2H), 6.580 (d, J=8 Hz, 1H),6.724 (d, J=8 Hz, 1H), 7.428 (t, J=8 Hz, 1H), 7.796 (br. s, 1H), 8.329(br. s, 1H), 10.922 (s, 1H). MS 342 (MH⁺).

Example 224a: 8-(3-amino-2-cyanophenoxy)octyl acetate

A solution of 8-(2-cyano-3-nitrophenoxy)octyl acetate (802 μmol, 268 mg)(Example 214b) in EtOH (15 mL) was hydrogenated in an H-cube apparatususing 10% Pd/C as catalyst. The solution was evaporated to give8-(3-amino-2-cyanophenoxy)octyl acetate (244 mg, 244 mg). MS 305 (MH⁺⁾

Example 224b: 8-(2-cyano-3-nitrophenoxy)octyl Acetate

2-(8-hydroxyoctyloxy)-6-nitrobenzonitrile (804 μmol, 235 mg) (Example214c) was dissolved in dry DCM (10 mL), cooled to 0° C., and treatedsuccessively with pyridine (3.216 mmol, 260 μL) and acetyl chloride(1.608 mmol, 114 μL). The reaction mixture was stirred and allowed towarm slowly to room temperature. When the reaction was complete, thevolatiles were removed in vacuo and the crude product purified on silicagel (10% to 50% EtOAc in hexanes) to give the desired product (268 mg,100%). MS 335 (MH⁺).

Example 224c: 2-(8-hydroxyoctyloxy)-6-nitrobenzonitrile

To a solution of 1,8-octanediol (3.87 mmol, 566 mg) in THF (dry, 10 mL)was added 2,6-dinitrobenzonitrile (1.29 mmol, 250 mg) and DBU (1.30mmol, 194 μL). The reaction mixture was stirred for 24 hours at roomtemperature an evaporated. The oily residue was triturated with 10%citric acid/water and solid NaCl added. The precipitate was collected,washed with water, dried in vacuo and purified on silica gel (40% to100% EtOAc in hexanes) to give the desired product (235 mg, 62.3%) as apinkish solid. MS 293 (MH⁺).

Example 225:N-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-2-hydroxy-2-methylpropanamide

Prepared as in Example 224 from1-(6-(3-amino-2-cyanophenoxy)hexylamino)-2-methyl-1-oxopropan-2-ylacetate (Example 225a) in 65.5% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.201(s, 6H), 1.289 (m, 2H), 1.399 (m, 4H), 1.790 (pentet, J=7 Hz, 2H), 3.036(q, J=6 Hz, 2H), 4.130 (t, J=6 Hz, 2H), 5.272 (s, 1H), 6.587 (d, J=8 Hz,1H), 6.728 (d, J=8 Hz, 1H), 7.436 (t, J=8 Hz, 1H), 7.594 (br. t, 1H),7.804 (br. s, 1H), 8.326 (br. s, 1H), 10.924 (s, 1H). MS 399 (MH⁺).

Example 225a:1-(6-(3-amino-2-cyanophenoxy)hexylamino)-2-methyl-1-oxopropan-2-ylacetate

Prepared as in Example 224a from1-(6-(2-cyano-3-nitrophenoxy)hexylamino)-2-methyl-1-oxopropan-2-ylacetate (Example 225b) in 94.4% yield. MS 362 (MH⁺). Example 225b:1-(6-(2-cyano-3-nitrophenoxy)hexylamino)-2-methyl-1-oxopropan-2-ylacetate

To a solution of tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate(333 μmol, 121 mg) (Example 225c) in dioxane (2 mL) was added con. HCl(1 mL). After 15 minutes, the solution was concentrated in vacuo anddried on high vacuum. The crude HCl salt was suspended in DCM (dry, 10mL) and treated with pyridine (2.664 mmol, 62 μL) and1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.332 mmol, 193 μL). Thereaction mixture was refluxed under a nitrogen atmosphere until clear (6h), then cooled to room temperature and the volatiles removed in vacuo.The residue was purified on silica gel (40% to 100% EtOAc in hexanes) togive the product (117 mg, 90%) as a light yellow heavy oil. MS 392(MH⁺).

Example 225c: tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate

Prepared as in Example 197c from tert-butyl 6-hydroxyhexylcarbamate in53.8% yield as light yellow solid. MS 364 (MH⁺).

Example 226:1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)urea

A solution of1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea(122 μmol, 58 mg) (Example 227) in DCM (2.5 mL) was treated with TFA(2.5 mL). The reaction mixture was stirred at room temperature for 4hours, then the volatiles were removed under a stream of nitrogen. Theoily residue was triturated with ether, the precipitate collected,washed with ether, then dissolved in MeOH and evaporated to gives thedesired product (44 mg, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ1.364(m, 6H), 1.812 (pentet, J=7 Hz, 2H), 2.943 (br t, 2H), 4.154 (d, J=7 Hz,2H), 4.131 (t, J=7 Hz, 2H), 5.349 (br. s, 2H), 5.894 (br. s, 1H), 6.607(d, J=8 Hz, 1H), 6.752 (d, J=8 Hz, 1H), 7.456 (t, J=8 Hz, 1H), 7.824(br. s, 1H), 8.351 (br. s, 1H), 10.945 (s, 1H). MS 356 (MH⁺).

Example 227:1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea

To a suspension of6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminiumchloride (25 μmol, 52 mg) (Example 228) in dry DCM (6 mL) wassuccessively added Et₃N (332 μmol, 46 μL) and1-(isocyanatomethyl)-4-methoxybenzene (183 μmol, 26 μL). The reactionwas stirred for 48 hours at room temperature then concentrated in vacuo.The residue was washed with water, dried, then purified on silica gel(20% to 100% EtOAc in hexanes) to give the desired product (64 mg, 81.0%yield). ¹H NMR (400 MHz, DMSO-d₆) δ1.296 (m, 2H), 1.371 (m, 4H), 1.791(pentet, J=8 Hz, 2H), 2.980 (q, J=6 Hz, 2H), 3.695 (s, 3H), 4.086 (d,J=6 Hz, 2H), 4.131 (t, J=6 Hz, 2H), 5.836 (br. t, J=5 Hz, 1H), 6.141(br. t, J=6 Hz, 1H), 6.585 (d, J=8 Hz, 1H), 6.727 (d, J=8 Hz, 1H), 6.840(d, J=9 Hz, 2H), 7.137 (d, J=9 Hz, 2H), 7.433 (t, J=8 Hz, 1H), 7.803(br. s, 1H), 8.321 (br. s, 1H), 10.926 (s, 1H). MS 476 (MH⁺).

Example 228:6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminiumChloride

To a solution of tert-butyl6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexylcarbamate(118 mg, 286 umol) (Example 229) in dioxane (2 mL) was added con. HCl (1mL) and the solution stirred at room temperature for 15 minutes. Thesolvents were removed in vacuo and the residue triturated with hotethanol. After cooling to room temperature, the precipitated wascollected, washed with hot ethanol, and dried in vacuo to give thedesired product 56 mg (62.9%) as an off-white powder. ¹H NMR (400 MHz,DMSO-d₆) δ1.367 (m, 4H), 1.529 (pentet, J=7 Hz, 2H), 1.795 (pentet, J=7Hz, 2H), 2.741 (br m, 2H), 4.144 (t, J=7 Hz, 2H), 6.596 (d, J=8 Hz, 1H),6.733 (d, J=8 Hz, 1H), 7.440 (t, J=8 Hz, 1H), 7.725 (br. s, 3H), 7.795(br. s, 1H), 8.350 (br. s, 1H), 10.954 (s, 1H). MS 313 (MH⁺).

Example 229: tert-butyl6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexylcarbamate

Prepared as in Example 224 from tert-butyl6-(3-amino-2-cyanophenoxy)hexylcarbamate (Example 229a) and sulfamoylchloride in 59.5% yield. ¹H NMR (400 MHz, DMSO-d₆) δ1.274 (m, 2H), 1.339(s, 9H), 1.361 (m, 4H), 1.779 (pentet, J=7 Hz, 2H), 2.878 (q, J=6 Hz,2H), 4.122 (t, J=6 Hz, 2H), 6.580 (d, J=8 Hz, 1H), 6.722 (d, J=8 Hz,1H), 6.75 (br t, J=6 Hz, 1H), 7.428 (t, J=8 Hz, 1H), 7.798 (br. s, 1H),8.323 (br. s, 1H), 10.921 (s, 1H). MS 413 (MH⁺).

Example 229a: tert-butyl 6-(3-amino-2-cyanophenoxy)hexylcarbamate

Prepared as in Example 224a from tert-butyl6-(2-cyano-3-nitrophenoxy)hexylcarbamate (example 225c) in quantitativeyield. MS 334 (MH⁺).

Example 230:5-(2-(1H-pyrrol-1-yl)ethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 224 from2-(2-(1H-pyrrol-1-yl)ethoxy)-6-aminobenzonitrile (Example 230a) andsulfamoyl chloride in 66.6% yield. ¹H NMR (400 MHz, DMSO-d₆) δ4.392 (m,4H), 5.992 (t, J=2 Hz, 2H), 6.595 (d, J=8 Hz, 1H), 6.693 (d, J=8 Hz,1H), 6.816 (t, J=2 Hz, 2H), 7.428 (t, J=8 Hz, 1H), 7.482 (br. s, 1H),8.288 (br. s, 1H), 10.930 (s, 1H). MS 307 (MH⁺).

Example 230a: 2-(2-(1H-pyrrol-1-yl)ethoxy)-6-aminobenzonitrile

Prepared as in Example 224a from2-(2-(1H-pyrrol-1-yl)ethoxy)-6-nitrobenzonitrile (Example 230b) in 85.2%yield. MS 228 (MH⁺).

Example 230b: 2-(2-(1H-pyrrol-1-yl)ethoxy)-6-nitrobenzonitrile

Prepared as in Example 160d from 2-(1H-pyrrol-1-yl)ethanol and2,6-dinitrobenzonitrile, in 42.5% yield. MS 258 (MH⁺).

Example 231:5-(2-(1H-pyrazol-1-yl)ethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 224 from2-(2-(1H-pyrazol-1-yl)ethoxy)-6-aminobenzonitrile (Example 231a) andsulfamoyl chloride in 54.5% yield. ¹H NMR (400 MHz, DMSO-d₆) δ4.406 (t,J=5 Hz, 2H), 4.630 (t, J=5 Hz, 2H), 6.266 (t, J=2 Hz, 1H), 6.593 (d, J=8Hz, 1H), 6.689 (d, J=8 Hz, 1H), 7.445 (br s, 1H), 7.425 (t, J=8 Hz, 1H),7.805 (d, J=2 Hz, 1H), 8.224 (br. s, 1H), 8.301 (br. s, 1H), 10.904 (s,1H). MS 308 (MH⁺).

Example 231a: 2-(2-(1H-pyrazol-1-yl)ethoxy)-6-aminobenzonitrile

Prepared as in Example 224a from2-(2-(1H-pyrazol-1-yl)ethoxy)-6-nitrobenzonitrile (Example 231b) in46.2% yield. MS 229 (MH⁺).

Example 231b: 2-(2-(1H-pyrazol-1-yl)ethoxy)-6-nitrobenzonitrile

Prepared as in Example 197197c from 2-(1H-pyrazol-1-yl)ethanol and2,6-dinitrobenzonitrile in 89.2% yield. MS 259 (MH⁺).

Example 232:5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 224 from2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-6-aminobenzonitrile (Example232a) and sulfamoyl chloride in 18.2% yield. ¹H NMR (400 MHz, DMSO-d₆)δ2.066 (s, 3H), 2.215 (s, 3H), 4.313 (t, J=4 Hz, 2H), 4.397 (t, J=4 Hz,2H), 5.801 (s, 1H), 6.584 (d, J=8 Hz, 1H), 6.645 (d, J=8 Hz, 1H), 7.418(t, J=8 Hz, 1H), 8.395 (br. s, 1H), 8.677 (br. s, 1H), 10.885 (s, 1H).MS 336 (MH⁺).

Example 232a:2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-6-aminobenzonitrile

Prepared as in Example 224a from2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-6-nitrobenzonitrile (example232b) in 69.3% yield. MS 257 (MH⁺).

Example 232b:2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-6-nitrobenzonitrile

Prepared as in Example 197c from 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanoland 2,6-dinitrobenzonitrile in 90.7% yield. MS 287 (MH⁺).

Example 233:5-(4-(methylthio)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 197 from2-sulfamoylamino-6-(4-(methylthio)butoxy)benzonitrile (Example 233a) in79% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.63-1.67 (m, 2H), 1.86-1.90 (m,2H), 2.02 (s, 3H), 2.48-2.53 (m, 2H), 4.16 (t, 2H), 6.57-6.60 (d, J=8.4Hz, 1H), 6.72-6.74 (d, J=8.4 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 7.80 (s,1H), 8.35 (s, 1H), 10.92 (s, 1H). MS 316 (MH⁺).

Example 233a: 2-sulfamoylamino-6-(4-(methylthio)butoxy)benzonitrile

Prepared as in Example 197a from2-amino-6-(4-(methylthio)-butoxy)benzonitrile (Example 233b) andsulfamoyl chloride in 66% yield. MS 316 (MH⁺).

Example 233b: 2-amino-6-(4-(methylthio)butoxy)benzonitrile

Prepared as in Example 197b (Method A) from2-(4-(methylthio)butoxy)-6-nitrobenzonitrile (Example 233c) in 95%yield. MS 237 (MH⁺).

Example 233c: 2-(4-(methylthio)butoxy)-6-nitrobenzonitrile

Prepared as in Example 197c from 4-(methylthio)butan-1-ol and2,6-dinitrobenzonitrile in 89% yield. MS 267 (MH⁺).

Example 234:5-(3-(methylthio)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 197 from2-sulfamoylamino-6-(3-(methylthio)propoxy)benzonitrile (Example 234a) in69% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 2.05 (s, 3H), 2.08 (m, 2H), 2.59(t, J=7.2 Hz, 2H), 4.21 (t, J=6.4 Hz, 2H), 6.59-6.61 (d, J=8.0 Hz, 1H),673-6.75 (d, J=8.8 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 8.33(s, 1H), 10.93 (s, 1H). MS 302 (MH⁺).

Example 234a: 2-sulfamoylamino-6-(3-(methylthio)propoxy)benzonitrile

Prepared as in Example 197a from2-amino-6-(3-(methylthio)propoxy)benzonitrile (Example 234b) andsulfamoyl chloride in 69% yield. MS 302 (MH⁺).

Example 234b: 2-amino-6-(3-(methylthio)propoxy)benzonitrile

Prepared as in Example 197b (Method A) from2-(3-(methylthio)propoxy)-6-nitrobenzonitrile (Example 234c) in 98%yield. MS 223 (MH⁺).

Example 234c: 2-(3-(methylthio)propoxy)-6-nitrobenzonitrile

Prepared as in Example 197c from 4-(methylthio)butan-1-ol and2,6-dinitrobenzonitrile in 89% yield. MS 253 (MH⁺).

Example 235:5-((2-methylcyclopropyl)methoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide

Prepared as in Example 157 from2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile sulfamide (example235a) in 68% yield (mixture of diastereoisomers). ¹H NMR (400 MHz,DMSO-d₆) δ 0.17-0.40 (m, 1H), 0.54-0.58 (m, 1H), 0.76-0.85 (m, 1H),0.99-1.12 (m, 4H), 3.96-4.33 (m, 2H), 6.58-6.61 (m, 1H), 6.67-6.77 (m,1H), 7.41-7.47 (m, 1H), 7.97 (s, NH), 8.38 (s, NH), 10.97 (s, NH). MS282 (MH⁺).

Example 235a: 2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrileSulfamide

Prepared as in Example 157a from2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile (Example 235b) in100% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 0.34-0.36 (m, 1H), 0.51-0.53 (m,1H), 0.77-0.79 (m, 1H), 0.95-0.97 (m, 1H), 1.04-1.09 (m, 3H), 3.92-4.03(m, 2H), 6.86-6.88 (bm, 1H), 7.11-7.18 (bm, 3H), 7.48-7.52 (bm, 1H),9.53 (bs, NH). MS 282 (MH⁺).

Example 235b: 2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile

A solution of 2-((2-methylcyclopropyl)methoxy)-6-nitrobenzonitrile(example 235c) (0.29 g, 1.25 mmol) in EtOAc/EtOH 1:1 (30 mL) washydrogenated in an H-cube apparatus using 10% Pd/C as catalyst. Thesolution was evaporated to give2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile (0.20 g, 79%) as ayellow oil. MS 203 (MH⁺).

Example 235c: 2-((2-methylcyclopropyl)methoxy)-6-nitrobenzonitrile

Example 236:4-Amino-5-(trans-2-methylcyclopentyloxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide

To a solution of 2-amino-6-(trans-2-methylcyclopentyloxy)benzonitrile(Example 236a) (150 mg, 0.694 mmol) in dimethylacetamide (3 mL) under N₂was added sulfamoyl chloride (3 equiv.). The reaction mixture wasstirred at room temperature under N₂ for 2 hours, diluted with ethylacetate (50 mL) and quenched with water (20 mL). The layers wereseparated. The organic extract was evaporated. Ethanol (3 mL) andaqueous NaOH (2N, 2.5 equiv.) were consecutively added to the residue.The resulting mixture was heated at 90° C. for 16 hours. The workup wasperformed as in Example 158 to provide the desired product (160 mg, 78%)as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ 1.02 (d, J=6.4 Hz, 3H),1.26 (m, 1H), 1.71 (br s, 3H), 1.89 (m, 1H), 2.12 (m, 1H), 2.24 (m, 1H),4.55 (br s, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.45(t, J=8.0 Hz, 1H), 7.73 (br s, 1H), 8.35 (br s, 1H), 10.96 (br s, 1H).MS 296 (MH⁺).

Example 236a: 2-Amino-6-(trans-2-methylcyclopentyloxy)benzonitrile

Prepared as in Example 158b from2-(trans-2-methylcyclopentyloxy)-6-nitrobenzonitrile (Example 236b) togive the title compound in quantitative yield as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 1.04 (d, J=7.2 Hz, 3H), 1.23 (m, 1H), 1.72 (m, 1H),1.81 (m, 2H), 1.99 (m, 2H), 2.26 (m, 1H), 4.28 (m, 1H), 4.36 (br s, 2H),6.18 (d, J=8.4 Hz, 1H), 6.18 (d, J=8.4 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H).MS 296 (MH⁺⁾

Example 236b: 2-(trans-2-Methylcyclopentyloxy)-6-nitrobenzonitrile

Prepared as in Example 158c from 2,6 dinitrobenzonitrile andtrans-2-methylcyclopentanol in 65% as a yellow solid. MS 247 (MH⁺).

Example 237:9-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)nonan-1-ol

Prepared as in Example 224 from 9-(3-amino-2-cyanophenoxy)nonyl acetate(Example 237a) and sulfamoyl chloride in 62.3% yield. ¹H NMR (400 MHz,DMSO-d₆) δ1.250 (m, 8H), 1.381 (m, 4H), 1.791 (pentet, J=7 Hz, 2H),3.349 (q, J=6 Hz, 2H), 4.135 (t, J=6 Hz, 2H), 4.301 (t, J=5 Hz, 1H),6.585 (d, J=8 Hz, 1H), 6.728 (d, J=8 Hz, 1H), 7.434 (t, J=8 Hz, 1H),7.798 (br. s, 1H), 8.329 (br. s, 1H), 10.924 (s, 1H). MS 356 (MH⁺).

Example 237a: 9-(3-amino-2-cyanophenoxy)nonyl Acetate

Prepared as in Example 224a from 9-(2-cyano-3-nitrophenoxy)nonyl acetate(Example 237b) in 99.3% yield. MS 319 (MH⁺).

Example 237b: 9-(2-cyano-3-nitrophenoxy)nonyl Acetate

Prepared as in Example 224b from2-(9-hydroxynonyloxy)-6-nitrobenzonitrile (Example 237c) in 100% yield.MS 349 (MH⁺).

Example 237c: 2-(9-hydroxynonyloxy)-6-nitrobenzonitrile

Prepared as in Example 224c (except DBU was replaced with1,1,3,3-tetramethylguanidine) from 1,9-nonanediol and2,6-dinitrobenzonitrile in 30.7% yield. MS 307 (MH⁺).

Photostability Tests Buffer Preparation

Aqueous buffer solution at pH 7.1 contains 50 mM potassium dihydrogenphosphate and ˜32 mM sodium hydroxide (solutions of 1.0 M hydrochloricacid and 1.0 M sodium hydroxide are used to adjust pH). Aqueous buffersolution at pH 4.0 contains 50 mM citric acid monosodium salt and ˜7.4mM sodium hydroxide (solutions of 1.0 M hydrochloric acid and 1.0 Msodium hydroxide are used to adjust pH). Aqueous buffer solution at pH2.8 contains 50 mM citric acid and −16 mM sodium hydroxide (solutions of1.0 M hydrochloric acid and 1.0 M sodium hydroxide are used to adjustpH).

Test Sample Preparation

The stock solutions of the test compounds at 25 mM are made bydissolving the compounds in dimethyl sulfoxide. The solutions of thestabilizers are made by dissolving the materials in the aqueous buffers.The stock solutions are then diluted to 25 μM with the stabilizersolutions to prepare the test solution and 4-mL aliquots of thesolutions are transferred to 20-mL clear glass vial for testing.

Photostability Tester Settings

Accelerated photodegradation was studied using a Q-Sun Xenon TestChamber (Q-Lab Model No. Xe-1-SC) at an irradiance setting of 350 mW/m²at 340 nm and temperature of 25 degrees Celsius. To put this inperspective, 24 hours of constant Q-Sun irradiation at these settings isapproximately equivalent to 12.4 days of direct sunlight in thesouthwestern United States. At 0, 1, 2, 4, and 6 hours from thebeginning of the radiation, a 0.4-mL aliquot from each vial is pippetedout to a 1-mL glass insert for analysis.

Sample Analysis and Data Analysis

The samples are analyzed using an Agilent 1100 LC/MSD equipped with aquaternary pump and a diode-array detector (DAD). The peak areas fromthe MSD chromatograms are used for quantitation, and the photostabilityis shown by plotting the percentages of the test compound which remainsintact at all time points. The peak areas from the DAD chromatograms areused for quantitation for stabilizers with concentration at 250 uM orhigher. The instrument conditions are listed below.

-   Column: YMC ODS AQ 3 um, 4.0×23 mm-   Column Temperature: Room temperature-   Auto-sampler Temperature: Room temperature-   Mobile Phase A: Water-   Mobile Phase B: Methanol-   Mobile Phase C: 1% Formic Acid-   Gradient: % C is constant at 5%; % B from 5% to 95% in 2 min, then    back to 5% at 2.1 min, and then held at 5% until 3.25 min; flow rate    is 2 mL/min-   Injection volume: 10 uL-   Data Collection time: 2.75 minutes-   MSD ion source: APCI-   MSD Signal settings: Positive, selected ion monitoring (SIM) at the    mass of the expected molecular ions.-   UV detection wavelength: 230 nm.-   MSD detection start time: 0.5 min

Compounds A, B, C, D, and E are five Examples as described above,wherein Compound A is an exemplary species of structural formula (II),while Compounds B, C, D, and E are exemplary species of structuralformula (I). More specifically, Compound E is an exemplary species ofstructural formula (Ie). For example, Compound B is Example 1.

A Q-Sun Xenon Test Chamber (Q-Lab Model No. Xe-1-SC), which reproducesthe entire spectrum of natural sunlight, was used to study thephoto-stability of Compounds A, B, C, and D in various mediums (with orwithout photostabilizers). The equivalent sunlight exposure time for 24hours in the Q-Sun at a constant temperature of 25° C. and irradiance of450 mW/m² @340 nm is estimated to be equivalent to approximately 15.9days of direct sunlight in the Southwestern United States.

FIG. 1 illustrates the effect of coffee and tea on rate ofphoto-degradation of Compound A relative to water alone. Specifically,Compound A showed remarkably improved stability to photo-degradation inboth brewed coffee and tea. By comparison, tert-butyl hydroquinone(TBHQ; 200 ppm in water) only has a marginal effect on the rate ofphoto-degradation of Compound A.

FIGS. 2 and 3 illustrate the photostability study of Compounds A and Bunder these condition: Direct sunlight was modeled using a Q-Sun XenonTest Chamber (Q-Lab Model No. Xe-1-SC) at an irradiance setting of 350mW/m² @ 340 nm, 25° C. Test samples were irradiated in the Q-Sun atthese settings in pH 2.8 buffer with/without Compounds A and B in thepresence/absence of the photo-stabilizers A (chlorogenic acid) and B(rutin, a.k.a. quercetin-3-rutinoside).

As shown by FIG. 2, Compound A can be stabilized from photo-breakdown inthe presence of either chlorogenic acid (i.e., Stabilizer A) or rutin(i.e., Stabilizer B). Chlorogenic acid and rutin are two representativephotostabilizers of the specific photostabilizers recited in thePhotostabilizer section herein above. In the absence of thephoto-stabilizer, 80% of Compound A was degraded after 6 hr ofirradiation (350 mW/m² @ 340 nm, 25° C.) in the Q-Sun system. Bycomparison, only 15% of Compound A was degraded in the presence of 100ppm of chlorogenic acid, and 45% of Compound A was degraded in thepresence of 25 ppm of rutin, under the same conditions.

As shown by FIG. 3, Compound B in solution can also be stabilized in thepresence of photostabilizer A or B under UV exposure. Without thestabilizer, about 80% of Compound B was degraded after 6 hr exposure toultraviolet (UV) radiation within the Q-Sun system. By comparison, only20% of Compound B was degraded in the presence of 100 ppm of chlorogenicacid, and 47% of Compound B was degraded in the presence of 25 ppm ofrutin, under the same conditions.

FIG. 4 shows some exemplary antioxidants that are suitable to bephotostabilizers. Some of those antioxidants are FEMA GRAS compounds.Table 1 below indicates the approved use levels for those FEMA GRAScompounds in non-alcoholic beverages.

TABLE 1 Usual use level/ Compound FEMA No. max use level (ppm) Phloretin4390  30/300 ppm Trilobatin 4674 100/100 ppm Naringin dihydrochalcone4495  50/60 ppm Neohesperidin 3811   5/10 ppm dihydrochalcone Naringin2769 NA Homoeriodictyol 4228 100/800 ppm Hesperetin 4313 100/800 ppmMyricitrin 4491  10/30 ppm EMIQ 4225 150/200 ppm Grape seed extract 4045100/200 ppm

FIG. 5 shows the time course of the photo-degradation of the sweetenhancer Compound A in the absence and the presence of several of theFEMA GRAS compounds with antioxidant properties. Direct sunlight wasmodeled using a Q-Sun Xenon Test Chamber (Q-Lab Model No. Xe-1-SC) at anirradiance setting of 350 mW/m² @ 340 nm, 25° C. Test samples wereirradiated in the Q-Sun at these settings in pH 2.8 buffer with CompoundA in the presence/absence of the photo-stabilizers. All of theantioxidants shown in FIG. 4 and Table 2 (below) are effective instabilizing Compound A to photo-oxidation. In one embodiment, EMIQ (200ppm) is particularly effective (72.64% remaining at 24 hrs).

TABLE 2 % % % % Conc Remaining @ Remaining @ Remaining @ Remaining @Antioxidant (ppm) 1 hr 2 hrs 4 hrs 6 hrs (none) — 65.43 40.68 18.39 8.95naringin   50 ppm 90.42 75.92 55.54 41.50 naringin   50 ppm 88.49 81.9562.54 50.56 dihydrochlacone neohesperidin   50 ppm 91.42 82.53 66.9556.72 dihydrochalcone trilobatin   50 ppm 90.34 81.41 64.75 51.47phloretin   25 ppm 89.62 80.75 64.60 50.64 homoeriodictol 12.5 ppm 90.8382.75 57.70 24.54 EMIQ  200 ppm 101.92 103.71 96.24 97.26 grape seedextract  100 ppm 89.43 77.83 61.29 49.64 myricitrin   50 ppm 95.06 91.0283.77 75.39

FIGS. 6A and 6B show the time course of photo-degradation of Compound Cand Compound D in the presence and absence of EMIQ. Compounds C and Dare analogs of Compound B. Similar to the photostability study ofCompound A, EMIQ (200 ppm) is very effective in retarding thephoto-degradation of both Compound C and Compound D out to at least 24hrs under conditions of accelerated photo-oxidation. As indicated byFIGS. 6A and 6B and Table 3 below, 86-90% of the compound remainedintact at 24 hrs in the presence of 200 ppm of EMIQ vs only 13-19%remaining in the absence of the antioxidant.

TABLE 3 % % % % % Remaining @ Remaining @ Remaining @ Remaining @Remaining @ Sample 1 hr 2 hrs 4 hrs 6 hrs 24 hrs 25 μM 99.43 96.00 92.2382.47 18.52 Compound C alone 25 μM 99.53 98.66 101.37 95.95 86.17Compound C + 200 ppm EMIQ 25 μM 98.26 94.99 85.99 76.72 12.75 Compound Dalone 25 μM 99.32 97.17 98.29 97.90 90.34 Compound D + 200 ppm EMIQ

FIG. 7 shows the chemical structures of some naturally occurringcinnamic acid and coumarin derivatives.

FIG. 8 shows the time course of the photo-degradation of Compound A inthe absence and the presence of the cinnamic acid and coumarinderivatives shown in FIG. 7. Direct sunlight was modeled using a Q-SunXenon Test Chamber (Q-Lab Model No. Xe-1-SC) at an irradiance setting of350 mW/m² @ 340 nm, 25° C. Test samples were irradiated in the Q-Sun atthese settings in pH 2.8 buffer with 25 μM of Compound A in thepresence/absence of the photo-stabilizers at a concentration of 100 ppm.All of the antioxidants shown in FIG. 8 and Table 4 are effective instabilizing Compound A to photo-oxidation. Daphnetin and sinapinic acidare particularly effective (>98% remaining at 6 hrs).

TABLE 4 % % % % Conc. Remaining Remaining Remaining RemainingAntioxidant (ppm) @ 1 hr @ 2 hrs @ 4 hrs @ 6 hrs (none) — 83.48 68.4549.18 32.82 ferulic acid 100 ppm 95.41 96.49 93.43 93.85 scopoletin 100ppm 103.59 104.11 100.07 95.72 caffeic acid 100 ppm 98.02 99.54 98.7495.55 daphnetin 100 ppm 99.13 99.76 98.13 98.45 sinapinic acid 100 ppm100.00 99.98 100.12 98.52

FIG. 9 and Table 5 show the time course of photo-degradation of CompoundC in the presence and absence of 50 and 100 ppm of daphnetin. Similar tothe photostability study of Compound A, daphnetin is effective inretarding the photo-degradation of Compound C for at least 7 hrs underconditions of accelerated photo-oxidation. In the presence of 100 ppm ofdaphnetin, 93.8% of the compound remained intact at 7 hrs vs only 66.49%remaining in the absence of the antioxidant.

TABLE 5 % % % % Remaining Remaining Remaining Remaining Sample @ 1 hr @2 hrs @ 4 hrs @ 7 hrs 25 μM Cmpd C 97.51 90.08 79.96 66.49 alone 25 μMCmpd C + 96.46 95.42 94.07 83.80 50 ppm daphnetin 25 μM Cmpd C + 97.6999.97 94.69 93.80 100 ppm daphnetin

Table 6 and FIG. 10 show the time course of the photo-degradation of thesweet enhancer Compound E in the absence and the presence of either EMIQor chlorogenic acid (“CGA”). Direct sunlight was modeled using a Q-SunXenon Test Chamber (Q-Lab Model No. Xe-1-SC) at an irradiance setting of350 mW/m² @ 340 nm, 25° C. Test samples were irradiated in the Q-Sun atthese settings in pH 2.8 buffer with sweet enhancer Compound E in thepresence/absence of the photostabilizers. In the presence of 200 ppm ofeither EMIQ or chlorogenic acid (CGA), the photo-degradation of CompoundE is effectively retarded for at least 24 hrs under conditions ofaccelerated photo-oxidation. In both cases, 81-86% of the compoundremained intact at 24 hrs in the presence of 200 ppm of the antioxidantsvs <1% remaining in the absence of the antioxidant.

TABLE 6 % % % % % Remaining @ Remaining @ Remaining @ Remaining @Remaining @ Sample 1 hr 2 hrs 4 hrs 6 hrs 24 hrs 25 uM Cmpd E 95.5286.61 68.39 50.35 0.29 alone 25 uM Cmpd E + 100.19 97.75 96.80 94.6781.22 200 ppm EMIQ 25 uM Cmpd E + 100.56 97.75 98.50 99.06 86.31 200 ppmCGA

All publications and patent applications herein are incorporated byreference to the same extent as if each individual publication or patentapplication was specifically and individually indicated to beincorporated by reference.

The foregoing detailed description has been given for clearness ofunderstanding only and no unnecessary limitations should be understoodtherefrom as modifications will be obvious to those skilled in the art.It is not an admission that any of the information provided herein isprior art or relevant to the presently claimed inventions, or that anypublication specifically or implicitly referenced is prior art.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those preferred embodiments may become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the invention unless otherwise indicatedherein or otherwise clearly contradicted by context.

We claim:
 1. A method of improving stability or reducing degradation ofa sweet enhancer in a liquid composition comprising contacting aphotostabilizer with the sweet enhancer in the liquid composition,wherein: the photostabilizer is selected from the group consisting of achromone derivative, a coumarine derivative, a phenylpropenioc carbonylcompound, and a combination thereof; and the sweet enhancer havingstructural formula (Ia) or (I′a), or a salt or solvate thereof:

wherein: A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R²,—NR¹C(O)NR²R³, —NR¹C(S)NR²R³ or —NR¹C(═NH)NR²R³; B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; C is —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₃R⁷, —C(O)NR⁷R⁸,—CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,—NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), —P(O)(R⁷)(OR⁸), orheteroaryl; R¹, R², R³, R⁷, R⁸, and R⁹ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively, R¹ and R², R² and R³, R⁷ and R⁸, orR⁸ and R⁹, together with the atoms to which they are bonded, form acycloheteroalkyl or substituted cycloheteroalkyl ring; R²¹ is hydrogen,alkyl, substituted alkyl, halo, —CN, —OR²⁵; R²² is hydrogen, alkyl,substituted alkyl, halo, —CN, —OR²⁷; R²³ is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,substituted acyl, halo, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —CN, —OR²⁹, —SR²⁹, —SOR²⁹, —SO₂R²⁹, —OC(O)R²⁹,—NR²⁹R³⁰, —C(O)NR²⁹R³⁰, —C(O)R²⁹, —CO₂R²⁹, —SO₂NR²⁹R³⁰, —NR²⁹SO₂R³⁰,—B(OR²⁹)(OR³⁰), —P(O)(OR²⁹)(OR³⁰) or —P(O)(R²⁹)(OR³⁰); R²⁴ is hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —CN, —OR³¹, —SR³¹, —SOR³¹, —SO₂R³¹,—OC(O)R³¹, —NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹, —CO₂R³¹, —SO₂NR³¹R³²,—NR³¹SO₂R³², —B(OR³¹)(OR³²), —P(O)(OR³¹)(OR³²) or —P(O)(R³¹)(OR³²); oralternatively R²³ and R²⁴, taken together with the atoms to which theyare attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring; and R²⁵, R²⁷,R²⁹, R³⁰, R³¹, and R³² are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;or alternatively R²⁵ and R²⁷, R²⁷ and R²⁹, R²⁹ and R³⁰, R²⁹ and R³¹, orR³¹ and R³², together with the atoms to which they are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring.
 2. A method ofimproving stability or reducing degradation of a sweet enhancer in aliquid composition comprising contacting a photostabilizer with thesweet enhancer in the liquid composition, wherein: the photostabilizeris selected from the group consisting of a chromone derivative, acoumarine derivative, a phenylpropenioc carbonyl compound, and acombination thereof; and the sweet enhancer having structural formula(Ib) or (I′b), or a salt or solvate thereof:

wherein: A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R²,—NR¹C(O)NR²R³, —NR¹C(S)NR²R³ or —NR¹C(═NH)NR²R³; B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; C is —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₃R⁷, —C(O)NR⁷R⁸,—CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,—NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), —P(O)(R⁷)(OR⁸), orheteroaryl; R¹, R², R³, R⁷, R⁸, and R⁹ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively, R¹ and R², R² and R³, R⁷ and R⁸, orR⁸ and R⁹, together with the atoms to which they are bonded, form acycloheteroalkyl or substituted cycloheteroalkyl ring; L¹ is alkylene orsubstituted alkylene; L² is —NR³⁴—, —O—, —S—, —NR³⁴—C(O)—, —C(O)—NR³⁴—,—O—C(O)—, —C(O)—O—, —NR³⁴—C(O)—O—, —O—C(O)—NR³⁴—, —NR³⁴—C(O)—NR³⁵—,—O—C(O)—O—, -heterocyclylene-C(O)—, or -(substitutedheterocyclylene)-C(O)—; R³³ is alkyl, substituted alkyl, carbocyclyl,substituted carbocyclyl; aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heterocyclyl, substituted heterocyclyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, or substituted heteroarylalkyl; and R³⁴ and R³⁵ areindependently hydrogen, alkyl, substituted alkyl, carbocyclyl,substituted carbocyclyl; aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heterocyclyl, substituted heterocyclyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, or substituted heteroarylalkyl.
 3. A method ofimproving stability or reducing degradation of a sweet enhancer in aliquid composition comprising contacting a photostabilizer with thesweet enhancer in the liquid composition, wherein: the photostabilizeris selected from the group consisting of a chromone derivative, acoumarine derivative, a phenylpropenioc carbonyl compound, and acombination thereof; and the sweet enhancer having structural formula(Ic), (I′c), (Id), or (I′d), or a salt or solvate thereof:

wherein: A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R²,—NR¹C(O)NR²R³, —NR¹C(S)NR²R³ or —NR¹C(═NH)NR²R³; B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; C is —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₃R⁷, —C(O)NR⁷R⁸,—CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,—NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), —P(O)(R⁷)(OR⁸), orheteroaryl; R¹, R², R³, R⁷, R⁸, and R⁹ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively, R¹ and R², R² and R³, R⁷ and R⁸, orR⁸ and R⁹, together with the atoms to which they are bonded, form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R³³ is alkyl,substituted alkyl, carbocyclyl, substituted carbocyclyl; aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.
 4. A method of improving stability or reducingdegradation of a sweet enhancer in a liquid composition comprisingcontacting a photostabilizer with the sweet enhancer in the liquidcomposition, wherein: the photostabilizer is selected from the groupconsisting of a chromone derivative, a coumarine derivative, aphenylpropenioc carbonyl compound, and a combination thereof; and thesweet enhancer having structural formula (Ie), or a salt or solvatethereof:

wherein: R¹ and R² are independently hydrogen or C₁ to C₆ alkyl; L is C₁to C₁₂ alkylene or substituted C₁ to C₁₂ alkylene; M is —NR⁴—C(O)— or—C(O)—NR⁴—; R⁴ is hydrogen or C₁ to C₆ alkyl; or alternatively, when Mis —NR⁴—C(O)—, R⁴ and one or more atoms of L, together with the nitrogento which they are attached, form a 5- to 8-membered heterocyclic ringwhich is optionally substituted and contains one to three heteroatomsselected from nitrogen, oxygen, and sulfur; and R³ is C₁ to C₁₂ alkyl,substituted C₁ to C₁₂ alkyl, 5- to 8-membered heterocyclyl, orsubstituted 5- to 8-membered heterocyclyl; or alternatively, when M is—C(O)—NR⁴—, R⁴ and one or more atoms of R³, together with the nitrogento which they are attached, form a 5- to 8-membered heterocyclic ringwhich is optionally substituted and contains one to three heteroatomsselected from nitrogen, oxygen, and sulfur.
 5. The method of claim 4,wherein the compound of formula (Ie) is represented by structuralFormula (IeB):

wherein: L is C₁ to C₁₂ alkylene or substituted C₁ to C₁₂ alkylene; R⁴is hydrogen or C₁ to C₆ alkyl; and R³ is C₁ to C₁₂ alkyl, substituted C₁to C₁₂ alkyl, 5- to 8-membered heterocyclyl, substituted 5- to8-membered heterocyclyl; or alternatively, R⁴ and one or more atoms ofR³, together with the nitrogen to which they are attached, form a 5- to8-membered heterocyclic ring which is optionally substituted andcontains one to three heteroatoms selected from nitrogen, oxygen, andsulfur.
 6. A method of improving stability or reducing degradation of asweet enhancer in a liquid composition comprising contacting aphotostabilizer with the sweet enhancer in the liquid composition,wherein: the photostabilizer is selected from the group consisting of achromone derivative, a coumarine derivative, a phenylpropenioc carbonylcompound, and a combination thereof; and the sweet enhancer havingstructural formula selected from the group consisting of

or a salt or solvate of any of the foregoing.